3. Monogenetic causes of ADHD

Monogenetic causes refers to genes in which certain gene variants can trigger disorders that are associated with ADHD symptoms.
In rare cases, a single genetic defect can lead to ADHD.¹
We have also included chromosomal aberrations here, although these affect all genes of the chromosome and are therefore not a monogenetic cause. However, they are a monocausal genetic cause, which is why we have included them in this context.

As a gene can have various mutations, which (in the case of protein-coding genes) can cause a wide range of changes in protein activity (no protein activity at all, slightly reduced, normal, slightly increased, greatly increased…), monogenetic diseases can also occur in different forms or manifestations. Therefore, not every gene mutation of one of the genes mentioned here leads to ADHD. We have included genes with a significantly increased prevalence of ADHD in certain variants as a monogenetic cause of ADHD. The numbers in brackets indicate the ADHD prevalence for certain gene variants of the named gene. The figures should be viewed with caution, particularly in the case of very low numbers of affected individuals.

In addition to the genes listed here, there are several animal models in which a single gene has been deactivated and which develop ADHD symptoms (up to full-blown ADHD) as a result. These genes also represent monogenetic causes of ADHD.
Many monogenetic disorders are rare (orphan) diseases. Around 8,000 rare diseases are currently known. ICD-10 has only listed around 500 of these as separate codes. ICD 11 will go much further here.²

The gene candidates mentioned below only very rarely appear as dysfunctional gene variants. ADHD is not generally considered to be a monogenetic disorder. However, we believe it is quite possible that monogenetic causes could explain a relevant proportion of ADHD cases.

The percentages in the headings indicate the prevalence of ADHD among people with ADHD of the respective dysfunctional gene variant.

• 1. Monogenetic causes of ADHD
  • 1.1. FMR1, fragile X syndrome, FXS (full mutation: 42 to 59 %; premutation: 93 %)
  • 1.2. CAPRIN1, Cell Cycle Associated Protein 1 (82 %)
  • 1.3. PHF21A, PHD Finger Protein 21A (78 %)
  • 1.4. CHD2, Chromodomain Helicase DNA Binding Protein 2 (65 %)
  • 1.5. SETBP1 haploinsufficiency (65 %)
  • 1.6. DYRK1A, dual-specificity tyrosine phosphorylation-regulated kinase 1A (62 %)
  • 1.7. TSC1, TSC Complex Subunit 1 (30 to 60 %)
  • 1.8. ANK3, ANKYRIN 3 (57 %)
  • 1.9. NF1, neurofibromatosis type 1 (28.9 % to 53.8 %)
  • 1.10. Noonan syndrome spectrum disorders (51.1 %)
  • 1.11. THRB, thyroid hormone β-receptor gene (50 %)
  • 1.12. CHD8-NDD (approx. 50 %)
  • 1.13. SHANK2 (50 %)
  • 1.14. ANKRD11, Ankyrin Repeat Domain Containing 11, KBG syndrome (24 % to 41 %)
  • 1.15. PAH, PKU, phenylketonuria (38 % to 40 %)
  • 1.16. SRRM2, Serine/Arginine Repetitive Matrix 2 (36 % ?)
  • 1.17. DMD, dystrophinopathy, muscular dystrophy, muscle weakness (up to 32 %)
  • 1.18. NSD1, Sotos syndrome (31.7 %)
  • 1.19. MEFV, Familial Mediterranean Fever, FMF (31 %)
  • 1.20. ZMIZ1 loss of function (20 % to 28 %)
  • 1.21. MBOAT7 encephalopathy (26.6 % ?)
  • 1.22. BSN, Bassoon (25 %)
  • 1.23. FOLR1, cerebral folate transporter deficiency (22.2 % ?)
  • 1.24. CFTR, CNFTR, cystic fibrosis, cystic fibrosis (5.26 % to 21.9 %)
  • 1.25. NRXN1 Exonic deletion (10 to 20 %)
  • 1.26. ANKRD17, Ankyrin Repeat Domain Containing 17
  • 1.27. KMT2B, lysine methyltransferase 2B
  • 1.28. H1-4, Rahman syndrome
  • 1.29. SATB2
  • 1.30. ODC1, ornithine decarboxylase 1, Bachmann-Bupp syndrome, BABS
  • 1.31. CYP27A1, cerebrotendinous xanthomatosis, CTX
  • 1.32. SMAD4, Myhre
  • 1.33. SETD5
  • 1.34. RUNX1T1
  • 1.35. ARID1B haploinsufficiency
  • 1.36. Congenital disorder of glycosylation, CDG
    • 1.36.1. Transferrin, TF
    • 1.36.2. STT3A, STT3 Oligosaccharyltransferase Complex Catalytic Subunit A
    • 1.36.3. COG6
  • 1.37. PTS-related tetrahydrobiopterin deficiency, PTPSD
  • 1.38. Glucose-6-phosphate dehydrogenase deficiency (G6PD)
  • 1.39. Creatine deficit disorders
  • 1.40. Argininosuccinate lyase deficiency (ASLD)
• 2. Monogenetic animal models for ADHD symptoms
  • 2.1. Monogenetic causes of hyperactivity
  • 2.2. Monogenetic causes of hyperactivity and hypoactivity
  • 2.3. Monogenetic causes of impulsivity
  • 2.4. Monogenetic causes of attention problems
• 3. Chromosomal aberrations as causes of ADHD
  • 3.1. Sex chromosome aneuploidy: 48,XXY; 48,XXX; 48,XYY and 48,XXYY (up to 72%)
  • 3.2. Klinefelter syndrome (47,XXY) (25 % to 63 %)
  • 3.3. Trisomy 21, Down syndrome (14.6 % to over 50 %)
  • 3.4. 22Q11.2 duplication syndrome (18.2 % to 44 %)
  • 3.5. 22Q11.2 deletion syndrome (6 % to 37 %)
  • 3.6. Q11.23 deletion, Williams syndrome (64.7 % to 84 %)

1. Monogenetic causes of ADHD¶

1.1. FMR1, fragile X syndrome, FXS (full mutation: 42 to 59 %; premutation: 93 %)¶

The prevalence of fragile X syndrome is:

• Full mutation
  • 1 in 3,600 to 1 in 4,000 for men and approx. 1 in 4,000 to 1 in 6,000 for women³
  • 1 in 7,140 men and 1 in 11,000 women⁴
• Premutation
  • 1 in 855 for men and 1 in 291 for women⁴

Fragile X syndrome is the most common inherited cause of mental disability after trisomy 21 (Down syndrome).³

Fragile X syndrome (FXS) is caused by a full mutational expansion (more than 200 CGG repeats) in the FMR1 gene, resulting in a deficiency of the fragile X mental retardation protein (FRMP).⁵ Although most individuals with the premutation (55 to 200 CGG repeats) are considered unaffected by FXS, recent case studies have documented children with the premutation exhibiting cognitive deficits, behavioral problems, and/or autism spectrum disorders. ⁵
The missing FMRP

• impairs DAGL transport and the formation of functional postsynaptic mGluR5-DAGL complexes.⁶ This causes ectopic production of the endocannabinoid 2-AG, which in turn overstimulates the presynaptic CB1Rs and leads to their desensitization and internalization. The absence of FMRP impairs the on-demand release of 2-AG via DAGL. As a result, the effect of 2-AG on feedback inhibition and synaptic plasticity is absent. Thus, the regulation of glutamate and GABA signaling mediated by 2-AG is impaired. The lack of synaptic plasticity impairs learning, memory and regulation of behavior and emotion.⁷
• impairs homeostatic neuronal plasticity by blocking synaptic retinoic acid signaling⁸
  • Retinoic acid receptors influence the dopamine balance; see also Retinoic acid receptors influence the dopamine system In the article What regulates dopamine in the subsection Dopamine in the section Neurotransmitters in ADHD in the chapter Neurological aspects

Fragile X syndrome is considered a monogenetic cause of ASD.
The incidence of ADHD and mental retardation is also increased⁹
ADHD prevalence:

• 54 to 59 % in a study of 63 boys with the full mutation¹⁰
• 42 % in a study of 31 boys¹¹
• 93 % of 43 boys with the premutation showed ADHD symptoms. 79% showed ASD symptoms. The carriers of the premutation showed developmental problems, especially those who had clinical behavioral problems⁵

One study found no correlation between FMR1 pre-mutation and ADHD or anxiety in women (8% increased risk)¹², with only diagnostic prevalence determined, which can be misleading for under-diagnosed disorders such as ADHD.¹³

1.2. CAPRIN1, Cell Cycle Associated Protein 1 (82 %)¶

Prevalence: Only 15 people appear to have been found with CAPRIN1 haploinsufficiency so far.

Other names: Caprin-1; RNG105; GPI-Anchored Membrane Protein 1; GPIAP1; M11S1; Cytoplasmic Activation- And Proliferation-Associated Protein 1; Cytoplasmic Activation/Proliferation-Associated Protein-1; Membrane Component Chromosome 11 Surface Marker 1; GPI-Anchored Protein P137; RNA Granule Protein 105; GPI-P137; GPIP137; P137GPI; Membrane Component, Chromosome 11, Surface Marker 1; Activation/Proliferation-Associated Protein 1; Cell Cycle-Associated Protein 1; Caprin 1; GRIP137

The protein CAPRIN1 enables RNA-binding activity. CAPRIN1 may be involved in the negative regulation of translation and the positive regulation of dendritic spine morphogenesis. CAPRIN1 is located in the leading edge of the cell and in the cytosol.
CAPRIN1 is associated with

• Moyamoya angiopathy

Related paths:

• RNA binding
• RNA binding

Paralog: CAPRIN2

CAPRIN1 can regulate the transport and translation of mRNAs of proteins involved in synaptic plasticity in neurons and cell proliferation and migration in different cell types. CAPRIN1 binds directly and selectively to MYC and CCND2 RNAs. CAPRIN1 binds directly to several mRNAs associated with RNA granules in neuronal cells, including BDNF, CAMK2A, CREB1, MAP2, NTRK2 mRNAs as well as GRIN1 and KPNB1 mRNAs, but not to rRNAs.¹⁴

Haploinsufficiency of the CAPRIN1 gene is an autosomal dominant disorder associated with loss-of-function variants in cell cycle-associated protein 1 (CAPRIN1).
The CAPRIN1 protein regulates the transport and translation of neuronal mRNAs that are crucial for synaptic plasticity, as well as mRNAs encoding proteins that are important for cell proliferation and migration in different cell types.
CAPRIN1 variants with loss of function were associated with the following symptoms:¹⁵

• Speech impediment/speech delay (100 %)
• mental disability (83 %)
• ADHD (82 %)
• ASS (67 %)
• Respiratory problems (50 %)
• Anomalies of the limbs and skeleton (50%)
• Developmental delays (42%)
• Feeding problems (33 %)
• Seizures (33 %)
• Eye problems (33 %)

1.3. PHF21A, PHD Finger Protein 21A (78 %)¶

The prevalence of PHF21A dysfunction is unknown. Only around 20 cases have been reported to date. Unverifiable reports speak of a frequency of 1 in 1,100,000.

Other names: BHC80; KIAA1696; BM-006; BRAF35-HDAC Complex Protein BHC80; BHC80a; BRAF35/HDAC2 Complex (80 KDa); IDDBCS; NEDMS

The PHF21A gene encodes the protein BHC80, which is a component of the BHC complex. The BHC complex mediates the repression of neuron-specific genes in non-neuronal cells by the cis-regulatory element (repressor element-1, RE1; neural restrictive silencer, NRS, NRSE). The BHC complex is recruited by REST to RE1/NRSE sites and acts as a chromatin modifier by deacetylation and demethylation of specific sites on histones. In the BHC complex, BHC80 can act as a scaffold. BHC80 inhibits KDM1A-mediated demethylation of ‘Lys-4’ of histone H3 in vitro, suggesting a role in the regulation of demethylation.¹⁶

PHF21A is associated with:¹⁷

• Intellectual developmental disorder with behavioral abnormalities
  • heavy (37.5 %)
  • moderate (25 %)
  • mild (37.5 %)
• craniofacial dysmorphism with or without seizures
• Potocki-Shaffer syndrome
• epileptic phenotype (58.33 %)
• Developmental and epileptic encephalopathy (DEE) (71.42 %)
  • Of the 5 patients with DEE, three developed infantile epileptic seizure syndrome (IESS)
  • The seizures of 2 patients (2/5, 40 %) could be controlled with anti-seizure medication
• Overgrowth (100 % of 12 known people with ADHD)
• ADHD (77.78 % of 12 known people with ADHD)¹⁷, (4 of 5 persons with ADHD for whom information on ADHD was available = 80 %)¹⁸
• Hypotension (70 %)
• ASD (50 % of 12 known people with ADHD)¹⁷, (3 of 6 persons with ADHD for whom information on ADHD was available = 80 %)¹⁸
• Sleep disorders (33.33 %)

Related metabolic pathways:

• Infectious diseases
• Chromatin organization

Paralog: PHF21B

1.4. CHD2, Chromodomain Helicase DNA Binding Protein 2 (65 %)¶

Other names: Chromodomain Helicase DNA Binding Protein 2; ATP-Dependent Helicase CHD2; DKFZp686E01200 2; DKFZp547I1315; DKFZp781D1727; FLJ38614; CHD-2; EC 3.6.4.12; EC 3.6.1; DEE94; EEOC
The prevalence of CHD2 dysfunction is unknown. Only around 225 cases have been reported to date.

The CHD2 gene encodes an ATP-dependent enzyme that is involved in chromatin remodeling.
Pathogenic variants in CHD2 are very rare (orphan). There are 225 known diagnosed patients from 28 countries with various allelic variants in CHD2, including small intragenic deletions/insertions as well as missense, nonsense and splice site variants.¹⁹

65% (11 of 17) of the people with ADHD affected by CDH2 gene mutations showed ADHD, 57% ASD.¹⁹

1.5. SETBP1 haploinsufficiency (65 %)¶

The prevalence of SETBP1 haploinsufficiency is unknown. Only around 34 cases have been reported to date²⁰

All individuals with SETBP1 haploinsufficiency syndrome (SETBP1-HD) or SETBP1-related disorders (SETBP1-RD) had neurological impairments, including intellectual disability/developmental delay (IDD), attention-deficit/hyperactivity disorder, autism spectrum disorder and/or seizures, and speech and language delays.²¹
In SETBP1 haploinsufficiency syndrome, the following was found

• ADHD at 65 %
• ASD in 21 %, 75 % of whom also had comorbid ADHD

1.6. DYRK1A, dual-specificity tyrosine phosphorylation-regulated kinase 1A (62 %)¶

The prevalence of DYRK1A dysfunction is very low and is thought to be less than 1 in 1,100,000.

DYRK1A syndrome is a form of intellectual disability.
One study found evidence of ADHD in 18 out of 29 people with ADHD (62%)²²

Common symptoms of DYRK1A syndrome are:

• Mental disability
• Delayed speech development
• Motor problems
• Microcephaly (small head)
• Feeding problems
• Eye problems
• Behavioral problems
• Seizures
• Reduced height growth
• Autism symptoms

1.7. TSC1, TSC Complex Subunit 1 (30 to 60 %)¶

Other names: TSC Complex Subunit 1; Hamartin; KIAA0243; LAM; TSC; Tuberous Sclerosis 1 Protein; Tuberous Sclerosis 1, TSC-1
The prevalence of TSC1 dysfunctions is between 1:30,00 and 1:6,000.

TSC1 is probably a tumor suppressor gene that encodes the growth-inhibiting protein hamartin. Hamartin interacts with the GTPase-activating protein tuberin and stabilizes it. This hamartin-tuberin complex inhibits mTORC1 (Mammalian target of rapamycin complex 1) signaling, which is an important regulator of anabolic cell growth. Hamartin also acts as a co-chaperone for Hsp90, inhibiting its ATPase activity. Hamartin facilitates Hsp90-mediated folding of kinase and non-kinase clients, including TSC2, thereby preventing their ubiquitination and proteasomal degradation. TSC1 is involved in microtubule-mediated protein transport, but this appears to be due to unregulated mTOR signaling. TSC1 acts as a co-chaperone for HSP90AA1 and facilitates HSP90AA1 chaperoning of protein clients such as kinases, TSC2 and glucocorticoid receptor NR3C1. It increases ATP binding to HSP90AA1 and inhibits the ATPase activity of HSP90AA1. TSC1 competes with the activating co-chaperone AHSA1 for binding to HSP90AA1, resulting in a reciprocal regulatory mechanism for the chaperoning of client proteins. TSC1 recruits TSC2 to HSP90AA1 and stabilizes TSC2 by preventing the interaction between TSC2 and the ubiquitin ligase HERC1.²³

Tsc1-mTORC1 signaling controls striatal dopamine release And cognitive flexibility.²⁴

TSC1 is associated with

• tuberous sclerosis
• Lymphangioleiomyomatosis

Related signal paths:

• MTOR signaling
• Gene expression (transcription)

Tuberous sclerosis is associated with ADHD²⁵²⁶ in 30 to 60 % of people with ADHD and with neuropsychiatric manifestations such as ADHD, ASD or mental retardation in 90 %.²⁷
The Austrian Tuberous Sclerosis Association offers the TAND checklist for tuberous sclerosis on.

TSC2-KO mice also show tuberosclerosis-associated neuropsychiatric disorders and epilepsy. TSC2-KO mice showed more severe expressions of hyperactivity and cognitive disorders in females. TSC-associated disorders are thought to be caused by hyperactivation of the Mechanistic Target of Rapamycin Complex 1 (mTORC1). mTORC1 inhibitors ameliorate almost all TSC symptoms. The mTORC1 inhibitor sirolimus ameliorated TSC-associated neuropsychiatric disorders in TSC2-KO mice by modulating brain steroid levels and regulating E2/ERα-dependent transcriptional activation. Potentially, sirolimus could be useful for the treatment of TSC-associated neuropsychiatric disorders as well as diseases caused by sex differences and steroid levels.²⁸

1.8. ANK3, ANKYRIN 3 (57 %)¶

Other names: Ankyrin 3; Ankyrin 3, Node Of Ranvier (Ankyrin G); Ankyrin-G; Ankyrin-3; Ankyrin-3, Node Of Ranvier; ANKYRIN-G; MRT37; ANK-3

The prevalence of ANK3 dysfunction is extremely low. One source mentions 5 known cases worldwide²⁹, which, however, conflicts with the studies mentioned below³⁰, which cite higher prevalence figures.

The scaffold protein ankyrin-3 differs immunologically from the ankyrins ANK1 and ANK2. It is found at the axonal initial section and at the nodes of Ranvier of neurons in the central and peripheral nervous system. Within the nodes of Ranvier, where action potentials are actively transmitted, ANK3 is an intermediate binding partner for neurofascin and voltage-gated sodium channels. ANK3 is required for the normal accumulation of voltage-gated sodium channels at the axon hillock and for the initiation of action potentials.³¹ ANK2 encodes a protein involved in calcium ion transport across the plasma membrane.³²
In the human brain, ANK3 is found primarily in the cerebellum and, less densely, in the PFC, hippocampus, corpus callosum and hypothalamus. ANK3 plays a central role in regulating the localization of ion channels, membrane transporters, cell adhesion molecules and cytoskeletal proteins. ³³
There are connections between ANK3 and dopamine.³⁴³⁵ ANK3 is an essential component of AMPAR-mediated synaptic transmission and the maintenance of spine morphology. ANK3 promotes the stability of somatodendritic GABA-ergic synapses in vitro and in vivo by counteracting the endocytosis of GABAA receptors³⁶
ANK3 is expressed by oligodendrocytes, although it is found on the glial rather than the axonal side of the nodes.³⁷ ANK3 regulates the β-catenin/Wnt signaling pathway, which plays a role in bipolar Disorder.³⁸ A short ANK3 isoform is localized in dendritic spines and regulates NMDA receptor-dependent plasticity.³⁹ ANK3 accumulates in dendritic spines after chronic lithium treatment.⁴⁰ In bipolar Disorder, ANK3 mRNA is increased in the blood, although no increased expression was found in the brain.⁴¹

ANK3 and stress
Prenatal stress influences the interaction of the ANK3 protein with PSD95. ANK3 appears to influence the effects of early childhood stress on the development of psychiatric disorders.⁴²
Heterozygous ANK3+/- mice and mice in which ANK3 was deactivated in the dentate gyrus showed⁴³

• reduced anxiety
  • reversible through chronic lithium administration
• increased reward motivation
  • reversible through chronic lithium administration
    Ank3+/- mice showed an increased sensitivity to chronic stress:
• increased susceptibility to depression-like behaviors
• elevated corticosterone levels

ANK3 is associated with

• PTSD⁴⁴
• Autism⁴⁵⁴⁶
• Brugada syndrome, a form of cardiac arrhythmia.
• bipolar Disorder
  • e.g. rs10994336, rs1938526 and rs9804190³³
• mental disability.

OMIM: ANK3, ANKYRIN 3

ANK3 is associated with ADHD.⁴⁷ A study found this gene to be one of the 51 most likely gene candidates for ADHD.⁴⁸
ANK2 malformations correlated with a 5.55-fold risk of ADHD.³² The study assumes an ADHD prevalence in children of 5%, so this should result in an ADHD prevalence of 27.7% with an ANK2 malformation. This study also found that ANK2 caused a high ADHD-ASD comorbidity.

Among 27 persons with ADHD (16 people with monoallelic and 11 with biallelic ANK3 variants), the phenotype was found to be more severe in biallelic variants. Phenotypically were:³⁰

• Speech delay (92 %)
• ASS (76 %)
• mental disability (78 %)
• Hypotension (65 %)
• motor delay (68 %)
• ADHD (57%)
• Sleep disorders (50 %)
• Aggressiveness/self-harm (37.5 %)
• Epilepsy (35 %)
• Ataxia (11%, all with biallelic variants)

Most monoallelic variants lead to a shortened protein. The biallelic variants are almost exclusively missense mutations.
The mono- and biallelic variants appear to be localized differently in the three different ankyrin G isoforms, suggesting isoform-specific pathological mechanisms.

1.9. NF1, neurofibromatosis type 1 (28.9 % to 53.8 %)¶

Due to the large number of studies, the highest and lowest results were not taken into account when determining the prevalence stated in the title.

Other names: Von Recklinghausen’s disease, Recklinghausen’s disease, neurofibromatosis Recklinghausen, peripheral neurofibromatosis
Prevalence of around 1:3500 (0.029 %), one of the most common hereditary neurological diseases. Neurofibromatosis type 1 shows malformations of the skin and the central nervous system. Neurofibromatoses are nerve tumors.
Neurofibromatosis type 1 is a RASopathy.⁴⁹ Persons with ADHD with a Noonan syndrome spectrum disorder (NSSD) showed a comparable ADHD prevalence of 76.6 %.

Diagnostic criteria for neurofibromatosis type 1 are at least 2 of the following symptoms:⁵⁰

• Six or more café-au-lait (CAL) spots > 5 mm in diameter prepubertal and > 15 mm postpubertal.
• Freckling in the armpit or groin region.
• Two or more neurofibromas of any type or one plexiform neurofibroma (PNF)
• Glioma of the visual pathway
• Two or more iris nodules (detection by slit lamp examination) or two or more choroidal anomalies (CAs, detection as irregular bright nodules by optical coherence tomography, OCT, or near-infrared imaging, NIR imaging)
• Specific bony lesions such as sphenoid dysplasia, anterolateral bowing of the tibia or pseudarthrosis of the long tubular bones.
• A heterozygous pathogenic (= disease-causing) NF1 variant with an allele frequency of 50 % in normal tissue such as leukocytes.

ADHD is common in neurofibromatosis-1:

• 79.3 % among 29 children with NF1⁴⁹
  • ADHD-C 71.4%, ADHD-I 19.0%, ADHD-HI 9.5%
• 53,8 %: In a survey, n = 109 parents of children with neurofibromatosis reported severe ASD in 29.4 %, moderate to mild ASD in 26.6 % and AuADHD in 26 % to 53.8 %.⁵¹
• 49,4 %: A study of 93 children with neurofibromatosis-1 found ADHD in 46.⁵²
• 45,4 %: In a study of 531 people with ADHD with neurofibromatosis 1, information on ADHD was available for 207 subjects. Of these, 45.4 % had ADHD.⁵³ This corresponds to a 9-fold risk of ADHD⁵⁴
• 28,9 %: Among 128 persons with ADHD in neurofibromatosis type 1 (53.1% girls), 28.9% (37/128) were found to have ADHD, including 20 ADHD-C, 15 ADHD-I and 2 ADHD-HI. ADHD and ASD occur more frequently in neurofibromatosis type 1 ⁵⁵⁵⁶
  Other comorbidities of neurofibromatosis type 1 were macrocephaly (head circumference more than 2 SDs above the age average, 37.5 %), headache (18.6 %), cognitive impairment (7.8 %), motor deficits (6.2 %) and epilepsy (4.68 %). MRI revealed T2-weighted hyperintensities in the basal ganglia and/or cerebellum (70.5 %), optic nerve gliomas (25.8 %), plexiform neurofibromas (9.3 %), Chiari malformation type 1 (6.7 %), arachnoid cysts (5 %), gliomas of the central nervous system (3.1 %).⁵⁷
• 10.5 % at the age of 36 months: One study found ADHD in 10.5% of NF1-berioffected individuals by 36 months of age.⁵⁸
• A meta-analysis (k = 70, n = 3,653) found that children with NF1 had more severe symptoms of⁵⁹ compared to unaffected children in the parent rating
  • Inattention (Hedges g = 1.20)
  • Hyperactivity/impulsivity (Hedges g = 0.85)
  • combined ADHD symptoms (Hedges g = 1.02)

Larger Effect sizes for inattention and hyperactivity/impulsivity correlated with higher age and lower intelligence quotient (IQ).⁵⁹

NF1 children with ADHD and children with primary ADHD show similar deficits in attention and executive functions.
NF1 showed a slower reaction time and greater learning difficulties.⁶⁰

In 5 to 11% of people with NF-1, this is due to a microdeletion syndrome of neurofibromatosis type 1.
In 57 people with ADHD with NF-1 microdeletion syndrome:⁶¹

• 28 people with ADHD type 1, 4 type 2, 2 type 3, 9 atypical deletions and 14 persons with undetermined deletions
• in 33 out of 41 (80.5 %) learning difficulties
• 39 out of 49 (79.6 %) developmental delays
• expressive and/or receptive language delays in 35 of 49 (71.4 %)
• in 38 out of 56 (67.9 %) describable facial features
• in 23 of 42 (54.8 %) ADHD
• in 25 of 57 (43.8 %) plexiform neurofibromas
• in 3 of 57 (5.2 %) malignant peripheral nerve sheath tumors
• IQ decreased (between 50 and 96; 22 people with ADHD studied, 21 of whom were adults). Of the adults had:
  • 14 out of 21 (66.7 %) have a high school diploma
  • 4 out of 21 (19.0%) had some college experience.

In NF-1, dopamine deficiency correlates with learning difficulties.⁶² NF1 model mice showed reduced tyrosine hydroxylase expression in the striatum and VTA, 20% reduced dopamine levels in the hippocampus and 61% reduced DARPP32 phosphorylation. Postsynaptic D1 receptor expression in the hippocampus was unchanged. A D1 agonist was able to correct the resulting impairment of LTP.⁶²

The degradation of neurofibrin is regulated by the F-box protein FBXW11. Disorder of Fbxw11 by germline mutation or targeted genetic manipulation in the nucleus accumbens caused NF1 haploinsufficiency in male Nf1+/- mice:⁶³

• an increase in neurofibromin levels
• suppression of Ras-dependent ERK phosphorylation
• a correction of social learning deficits
• an improvement in impulsive behavior

1.10. Noonan syndrome spectrum disorders (51.1 %)¶

Noonan syndrome spectrum disorders (NSSD) are RASopathies. They are the Consequences of a monogenetic Disorder of various genes involved in the RAS/MAPK signaling pathway. People with ADHD are among others:

• PTPN11 (most common)
• SOS1
• RAF1
• RIT1
• KRAS
• NRAS
• BRAF

ADHD was found in 51.1% of people with ADHD.⁴⁹

1.11. THRB, thyroid hormone β-receptor gene (50 %)¶

The prevalence of THRB resistance is estimated at 1:19,000 to 1:40,000.⁶⁴

A (rarely occurring) genetic dysregulation of the TH beta receptor can cause increased blood thyroxine levels due to resistance to thyroid hormone β. 50% of people with ADHD show ADHD symptoms.⁶⁵
There was evidence of increased connectivity between regions of the default mode network and the dlPFC as well as weaker connectivity of the lingual gyrus to the bilateral insula (salience network). The former is associated with attention problems in ADHD, the latter with reduced habituation to visual stimuli and increased distractibility in ADHD.

Both hypothyroidism and hyperthyroidism cause cognitive changes. Depending on the degree of hypothyroidism, the cognitive effects can range from mild impairment of memory and attention to complete dementia. Hyperthyroidism can also cause inattention and hyperarousal, among other cognitive deficits.⁶⁶⁶⁷

THRB encodes the thyroid receptor isoforms TRβ1 and TRβ2, the THRA gene encodes the thyroid receptor alpha, TRα1.
The pituitary hormone TSH (thyroid-stimulating hormone) stimulates the thyroid gland to produce thyroxine (T4; prohormone) and then triiodothyronine (T3). The thyroid hormones (T3 and T4) in the blood in turn regulate the pituitary release of TSH within the hypothalamic-pituitary-thyroid axis, which is mediated by the receptor isoform TRβ2.
In the case of resistance to thyroid hormone β, this negative feedback loop, which stabilizes the TH level in the blood, is disrupted. This leads to increased TH and unsuppressed, i.e. normal TSH levels.⁶⁵

1.12. CHD8-NDD (approx. 50 %)¶

CHD8-related intellectual disability-autism-macrocephaly-tall stature syndrome is very rare, with 1 in 1,100,000 cases,{{Orpha.net:

CHD8-related neurodevelopmental disorder with overgrowth (CHD8-NDD) is characterized by⁶⁸

• general overgrowth
  • Macrocephaly (usually in infancy) (in approx. 80 %)
  • Tall stature (usually during puberty) (in approx. 80 %)
• Developmental delay/intellectual disability
  • most frequently speech and movement delays
  • if intellectual disability, usually only in the mild to moderate range
• Autism spectrum disorder (in approx. 75 to 80 %)
  - ADHD (in approx. 50 %)
• neuropsychiatric problems
• neurological problems
• Sleep disorders (for approx. 67 %)
  • delayed onset of sleep
  • frequent awakenings at night
• Gastrointestinal problems (approx. 66%)
  • Constipation with or without periods of diarrhea
• Hypotension (in approx. 30 %)
• Anxiety (29 %)
• Seizures (in approx. 10 to 15 %)
• Dystonia (rare)
• Chiari I malformation (rare)

1.13. SHANK2 (50 %)¶

SHANK2 is very rare.

A deletion or a pathogenic sequence variant of the SHANK2 gene causes a SHANK2 disorder. This is associated with ASD, mental retardation and developmental delays.
Among 10 people with ADHD were found:⁶⁹

• ASA at 90 % (0.2 % of all ASA cases⁷⁰ to 0.38 % of all ASA cases)⁷¹
• ADHD at 50%
• mild to moderate developmental delays
• sensory hyperreactivity and search behavior were more pronounced than sensory hyporeactivity
• Hypotension
• recurrent ear infections
• gastrointestinal anomalies
• no similar dysmorphic facial features
• significantly higher adaptive functional capacity than with PMS

1.14. ANKRD11, Ankyrin Repeat Domain Containing 11, KBG syndrome (24 % to 41 %)¶

Other names: ANCO1; ANCO-1; LZ16; T13; Ankyrin Repeat Domain-Containing Protein 11; Ankyrin Repeats Containing Cofactor 1; Ankyrin Repeat-Containing Cofactor 1; Ankyrin Repeat Domain 11; Nasopharyngeal Carcinoma Susceptibility Protein
ANKRD11 malfunctions are very rare. The prevalence is given as less than 1:1,000,000.

The ANKRD11 protein contains an ankyrin repeat domain. ANKRD11 inhibits the ligand-dependent activation of transcription. ANKRD11 is a chromatin regulator that modulates histone acetylation and gene expression in neural progenitor cells. ANKRD11 can recruit histone deacetylases (HDACs) to the p160 coactivator/nuclear receptor complex to inhibit ligand-dependent transactivation. ANKRD11 plays a role in the proliferation and development of cortical neural progenitor cells. ANKRD11 can regulate bone homeostasis.⁷²
ANKRD11 is associated with:

• rare genetic intellectual disabilities
• KBG syndrome
  • KBG is a rare syndrome. Genetic variants in ankyrin repeat domain 11 (ANKRD11) and deletions in 16q24.3 can cause KBG syndrome. In a group of 25 people with ADHD, 24% were diagnosed with ADHD.⁷³
    KBG goes hand in hand with⁷⁴
    • Macrodontia
    • pronounced craniofacial features
    • Short stature
    • Skeletal anomalies
    • global developmental delay
    • Seizures
    • mental disability
    • Hearing loss and/or middle ear infection
    • Visual disturbances
    • Cryptorchidism
    • Cardiopathy
    • Feeding problems

A survey of 91 people with ADHD revealed prevalence rates of⁷⁵

• 48 % Anxiety disorders
• 44 % Autism
• 41 % ADHD
• 37 % Hearing problems
• 37 % High level of frustration
• 36 % Visual disturbances
• 31 % seizures, of which
  • 52 % were currently able to control them with medication or a ketogenic diet
  • 30 % had treatment-resistant seizures
  • 22 % no longer had any seizures
  • none of the people with recent seizures lived independently
• 31 % Misaligned teeth
• 29 % Gastrointestinal problems in adulthood
  • of which all constipation
  • of which 73 % reflux
• 29 % Scoliosis
• 28% had difficulty falling asleep, almost half of whom needed medication such as melatonin to fall asleep
• 27 % Lordosis or kyphosis
• 26 % Problems sleeping through the night
• 26 % Outbursts of anger
• 25 % Aggression towards themselves or others
• 23 % Gastrointestinal problems in childhood
• 22 % Enamel problems
• 21 % increased need for sleep
• 19 % Problems with the palate
• 19 % Caries
• 19 % had too many teeth
• 19 % Depression
• 18 % Mood swings
• 18 % Sensory search behavior
• 15 % Hip problems
• 15 % binge eating
• 12 % Compulsions
• 12 % Tics
• 12 % Heart valve problems
• 11 % reduced appetite or anorexia
• 11 % Sensory avoidance behavior
• 9 % Sudden falling asleep during the day
• 9 % High blood pressure
• 8 % Regression (loss of previously acquired skills)
• 8 % Keloid scars
• 8 % Arthritis
• 8 % abnormal wound healing
• 5 % Osteoporosis
• 5 % Sleep apnea
• 4 % Restless legs syndrome.
• 4 % sudden drop in activity
• 1 % Schizophrenia
• 1 % Borderline personality disorder

1.15. PAH, PKU, phenylketonuria (38 % to 40 %)¶

Other names: Følling’s disease, Fölling’s disease, phenylpyruvic acid oligophrenia, oligophrenia phenylpyruvica, hyperphenylalaninemia
Prevalence: 1/8,000 (0.0125 %) to 1/16,000 (0.00625 &)

Based on an ADHD prevalence of 8%, this would result in an ADHD risk increase of + 375%.

Phenylketonuria (PKU) is a recessive disorder of phenylalanine metabolism due to mutations in the phenylalanine hydroxylase gene). PKU leads to a significant excess of phenylalanine (hyperphenylalaninemia). As phenylalanine and tyrosine pass through the blood-brain barrier via the same transporters, and these transporters have a higher affinity for phenylalanine, too little tyrosine reaches the brain if there is an excess of phenylalanine in the blood. Tyrosine is a precursor for dopamine, from which noradrenaline and adrenaline are further produced. An excess of phenylalanine in the blood therefore leads to a lack of dopamine, noradrenaline and adrenaline in the brain.⁷⁶⁷⁷ Excess phenylalanine also causes changes in cerebral myelin and protein synthesis as well as reduced levels of serotonin in the brain.⁷⁸ ADHD and phenylketonuria therefore have the common feature of a dopamine deficiency ^{79 8081}

A meta-analysis found ADHD and hyperactivity in 40% of people with ADHD (meta-analysis, k = 8, n = 222).⁸² A small study found an ADHD rate of 38% in phenylketonuria despite adequate treatment.⁸³

People with ADHD often show symptoms of ADHD, although the subtypes with hyperactivity seem to predominate.^8485798687

Treatment with sapropterin improved ADHD symptoms in a pharma-funded study in phenylketunorie.⁸⁸ One study also suggests BH4 treatment for ADHD, which is helpful for PKU.⁸¹

A low phenylalanine diet prevents most of the Consequences of phenylketonuria, but only if it is started within the first few weeks of life.
The neuronal developmental disorder caused by PKU is mediated, among other things, by the dopamine deficiency caused by PKU.⁸⁹ This is consistent with the dopaminergic developmental pathway of ADHD.⁹⁰ The fact that the low-phenylalanine diet can be discontinued in adulthood, i.e. when brain development is complete, also speaks in favor of a significant influence of dopamine deficiency on brain development in PKU.

1.16. SRRM2, Serine/Arginine Repetitive Matrix 2 (36 % ?)¶

Other names: Serine/Arginine Repetitive Matrix 2; SRL300; KIAA0324; SRm300; Cwc21; Serine/Arginine-Rich Splicing Factor-Related Nuclear Matrix Protein Of 300; KDa; Tax-Responsive Enhancer Element-Binding Protein 803; Ser/Arg-Related Nuclear Matrix Protein Of 300 KDa; SR-Related Nuclear Matrix Protein Of 300 KDa; Serine/Arginine Repetitive Matrix Protein; Splicing Coactivator Subunit SRm300; 300 KDa Nuclear Matrix Antigen; TaxREB803; Testicular Secretory Protein Li 53; RNA Binding Protein; HSPC075; 300-KD; SRM300; CWF21
SRRM2 malfunctions very rare. Among 1000 people with developmental delay and intellectual disability, 2 were found to have this genetic disorder. Intellectual disability has a prevalence of 1.65%, developmental delay has a prevalence of 6.5%.

SRRM2 is a protein-coding gene. It enables C2H2 zinc finger domain binding activity and protein N-terminus binding activity. SRRM2 is found in the Cajal body and nuclear speck. SRRM2 is involved in mRNA splicing as part of the U2-type catalytic step 2 spliceosome and the precatalytic U2 spliceosome. SRRM2 is a biomarker for Parkinson’s disease.⁹¹

SRRM2 is associated with:

• Status epilepticus
• Chondromalacia of Patella

Related signal paths:

• Processing of Capped Intron-Containing Pre-mRNA
• RNA binding
• C2H2 zinc finger domain binding

Paralog: MUC12

SRRM2 gene variants with loss of function show common clinical features:⁹²⁹³

• Developmental delay
  • to varying degrees
  • a connection with SRRM2 was found in 0.3% of all persons with ADHD
• ADHD
  • ADHD symptoms in 8 out of 22 people with ADHD⁹³
• Autism
• Macrocephaly
• Hypotension
• gastroesophageal reflux
• Overweight/obesity

1.17. DMD, dystrophinopathy, muscular dystrophy, muscle weakness (up to 32 %)¶

Dystrophinopathies are monogenetic disorders of the DMD gene on the X chromosome, which is why only boys are affected.
The population prevalence of Duchenne muscular dystrophy is 1 in 3,500 to 6,000⁹⁴, the prevalence of Becker muscular dystrophy is 1 in 16,700 to 18,500⁹⁵.

In dystrophinopathies (such as Duchenne muscular dystrophy - complete absence of dystrophin in muscle tissue ⁹⁶ or Becker muscular dystrophy - too low dystrophin levels⁹⁷ ), there was evidence of a greatly increased prevalence of ADHD⁹⁸ of 18.4 %⁹⁹¹⁰⁰ or 11.7 %¹⁰¹ to 9.8 % in Duchenne ¹⁰², of ASD of 6 %⁹⁹ to 12.73 %¹⁰⁰ (4.2 % in Duchenne¹⁰² ) and of mental retardation of 22 %.⁹⁹
Hyperactivity and/or inattention were found in 31.4% of people with ADHD.¹⁰³
Hyperactivity was found in 24% of the people with ADHD.¹⁰⁴
Inattention was found in 44% of people with ADHD.¹⁰⁴
Internalizing problems were found in 24% of the people with ADHD.¹⁰⁴
Externalizing problems were found in 15% of the people with ADHD.¹⁰⁴
Emotional and/or behavioral problems were found in 38.7% of the people with ADHD.¹⁰³
One review reported an ADHD risk in Duchenne of 11% to 32%, compared to 6% to 7% in the general population, representing an 83% to 357% increased risk of ADHD.¹⁰⁵
One study found only one case of ADHD among 36 Duchenne and 1 Becker person with ADHD.¹⁰⁶

1.18. NSD1, Sotos syndrome (31.7 %)¶

Sotos syndrome results from a malformation of the NSD1 gene and occurs de novo in 95% of cases. The prevalence is 1 in 14,000 births.

Symptoms:¹⁰⁷

• prenatal tall stature
• postnatal tall stature
• Macrosomia (weight of the child above the 95th percentile, 4350 g)
• excessive growth in the first 5 years of life, especially in the 2nd and 3rd year of life
• morphological bone age higher than the actual age
• muscular hypotension
• Dolichocephalus (longitudinal skull, excessive longitudinal growth of the skull)
• facial dysmorphia
• Hypertelorism
• little hair, receding hairline
• large forehead
• long, accentuated chin
• Orthopaedic problems (e.g. scoliosis, foot deformities)
• Developmental disorders (very different degrees)
  • motorized
  • cognitive
  • linguistic
• ADHD prevalence: total 31.7 % (13/41)
  • 53,8 % (7/13)¹⁰⁸
  • 21 % (6/28)¹⁰⁹
• ASA prevalence: total 29.3 % (12/41)
  • 30,8 % (4/13)¹⁰⁸
  • 28,5 % (8/28) ¹⁰⁹

1.19. MEFV, Familial Mediterranean Fever, FMF (31 %)¶

The prevalence of familial Mediterranean fever (FMF) is 1:20,000 worldwide.
In people of Armenian, Turkish, Arab and Sephardic-Jewish descent, the prevalence is between 1:300 and 1:100 (approx. 0.3% to 1%)
The prevalence of ADHD in FMF is 31%. (meta-analysis, k = 36, n = 907)¹¹⁰

FMF is caused monogenetically by mutations in the MEFV gene. The mutations lead to a malfunction of the protein pyrin. Pyrin regulates the inflammatory reaction.

FMF is a rare, hereditary autoinflammatory disease.
Symptoms:

• recurrent episodes of fever, abdominal, chest and joint pain
• Seizures usually short (1-3 days)
• people with ADHD feel free of symptoms in between

Comorbidities:

• Headaches (42.9 %)
• Muscle weakness, diplopia (35.7 %)
• Sensory disorders (35.7 %)
• Facial nerve palsy (14.3 %)
• Multiple sclerosis (28.6 %).
• ADHD (31 %)

Treatment:

• Colchicine to control relapses and prevent the serious complication of amyloidosis

1.20. ZMIZ1 loss of function (20 % to 28 %)¶

One study reports an ADHD rate among people with ADHD caused by ZMIZ1 gene variants (Zinc Finger MIZ-Type Containing 1) with loss of function of:¹¹¹

• TRP domain: 20 % (ASS: 60 %)
• Proline-rich domain: 22 % (67 %)
• Alainine-rich domain: 28 % (14 %)

The percentages were determined from the chart included.

ZMIZ1 is a chromatin remodeler and transcriptional activator¹¹¹
ZMIZ1 regulates, among other things

• Embryonic development
• Angiogenesis
• Immune response

1.21. MBOAT7 encephalopathy (26.6 % ?)¶

Out of 15 persons with ADHD encephalopathy, 4 showed attention problems (26.6%).¹¹²
MBOAT7 encephalopathy is associated with neurodevelopmental disorders, mental retardation, epilepsy and neuropsychiatric disorders such as ADHD and ASD.

1.22. BSN, Bassoon (25 %)¶

The prevalence of BSN de novo variants is unknown.

Of 29 persons with ADHD with a de novo variant of BSN; which encodes the presynaptic protein bassoon, showed¹¹³

• 49 % Epilepsy
• 38 % Developmental delay
• 34 % Obesity
• 28 % Speech delay
• 25 % ADHD
• 17 % ASS

1.23. FOLR1, cerebral folate transporter deficiency (22.2 % ?)¶

Among 9 persons with ADHD found, 2 were found to have ADHD (22.2%).¹¹⁴
The first abnormalities were febrile convulsions and ADHD symptoms. 44.4% suffered from ataxia and neuromotor and mental retardation,

1.24. CFTR, CNFTR, cystic fibrosis, cystic fibrosis (5.26 % to 21.9 %)¶

Other names: Gene of the ciliary neurotrophic factor receptor, CF transmembrane conductance regulator; DJ760C5.1; TNR-CFTR; CFTR/MRP; ABC35; ABCC7; MRP7; Cystic Fibrosis Transmembrane Conductance Regulator; Channel Conductance-Controlling ATPase; CAMP-Dependent Chloride Channel; CF; Cystic Fibrosis Transmembrane Conductance Regulator, ATP-Binding Cassette (Sub-Family C, Member 7); Cystic Fibrosis Transmembrane Conductance Regulator (ATP-Binding Cassette Sub-Family C, Member 7); Cystic Fibrosis Transmembrane Conductance Regulating; ATP-Binding Cassette Sub-Family C, Member 7; ATP-Binding Cassette Sub-Family C Member 7; EC 3.6.3.49; EC 5.6.1.6; EC 3.6.3

A CFTR gene malfunction is said to be present in 3 to 4 % of the population, i.e. in every 25th to 33rd person.¹¹⁵ Cystic fibrosis affects one in every 3,300 to 4,800 newborns.

Cystic fibrosis is associated with increased ADHD symptoms.¹¹⁶ Reported prevalence rates of ADHD in pwCF ranged from 5.26% to 21.9%.¹¹⁷

Cystic fibrosis correlates with mutations in the CFTR gene¹¹⁸, which has been identified as a gene candidate for ADHD.^119116120
CTFR-KO zebrafish show ADHD symptoms such as hyperactivity, impulsivity and attention problems.¹²¹

The protein CFTR encodes a member of the ATP-binding cassette transporter (ABC) superfamily. CFTR functions as a chloride channel, making it unique among members of this protein family, and controls the secretion and absorption of ions and water in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP binding by the nucleotide-binding domains and ATP hydrolysis. The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a protein that is fixed on the surface of cells, a so-called chloride channel. Mutations in the CFTR gene in humans lead to the absence or impaired function of the channel, which can cause cystic fibrosis and congenital aplasia of the vas deferens (CAVD). CFTR is an epithelial ion channel that plays an important role in the regulation of epithelial ion and water transport, fluid homeostasis (including airway homeostasis). CFTR mediates the transport of chloride ions across the cell membrane. Chloride channels are a family of anion-selective channels involved in a variety of biological processes, including regulation of neuronal, skeletal, cardiac and smooth muscle excitability, regulation of cell volume, transepithelial salt transport and acidification of intracellular and extracellular compartments. CFTR channel activity is coupled to ATP hydrolysis. The ion channel is also permeable to HCO(3)(-); the selectivity depends on the extracellular chloride concentration. CFTR also exerts its function by modulating the activity of other ion channels and transporters. CFTR contributes to the regulation of the pH and ionic content of the surface fluid layer of the airways and thus plays an important role in the defense against pathogens. CFTR modulates the activity of the epithelial sodium channel (ENaC) complex, in part by regulating the cell surface expression of the ENaC complex. CFTR inhibits the activity of the ENaC channel containing the subunits SCNN1A, SCNN1B and SCNN1G, as well as the activity of the ENaC channel containing the subunits SCNN1D, SCNN1B and SCNN1G, but not the ENaC channel containing the subunits SCNN1A, SCNN1B and SCNN1G. CFTR can regulate bicarbonate secretion and recycling in epithelial cells by regulating the transporter SLC4A7. CFTR can inhibit the chloride channel activity of ANO1. CFTR plays a role in chloride and bicarbonate homeostasis during epididymal maturation and capacitation of spermatozoa.¹¹⁸
CFTR is associated with

• Cystic fibrosis
  • Cystic fibrosis correlates with increased L-dopa levels in blood and urine.¹²² This is an indication of a link between cystic fibrosis and the dopamine balance. However, cystic fibrosis can have various genetic (co-)causes, so that it is not necessarily possible to draw conclusions about CFTR.
• Congenital bilateral aplasia of the vas deferens
• Cystic fibrosis
  • Cystic fibrosis is the most common fatal genetic Disorder in populations of Northern European descent.
  • The most common mutation in cystic fibrosis, DeltaF508, leads to impaired folding and transport of the encoded protein. Several pseudogenes have been identified in the human genome.

Related signal paths:

• wtCFTR
• delta508-CFTR traffic / Generic scheme (standard and CF)
• IL-1 Family Signaling Pathways
• Enzyme binding
• PDZ domain binding

Paralog: ABCC4

OMIM: Gene of the ciliary neurotrophic factor receptor CNFTR

CFTR (CNFTR) is a candidate gene for ADHD.¹¹⁹

1.25. NRXN1 Exonic deletion (10 to 20 %)¶

The prevalence of exonic NRXN1 deletions in the general Danish population was 0.07%, the prevalence of all NRXN1 deletions was 0.255%.¹²³
An English study found a prevalence of 0.039% and 0.07% respectively.¹²⁴

Exonic NRXN1 deletions correlated with

• increased risk of ADHD:
  • 4.68 times the risk of ADHD¹²⁵
  • 2.01-fold ADHD risk¹²³

Based on an ADHD prevalence of 5 to 10 %, we assume an ADHD risk of 10 to 20 %.

Non-exonic deletions were not associated with a significantly increased risk of ADHD.¹²³

Exonic NRXN1 deletions were also associated with a massively increased risk of other psychiatric disorders:

• 20.3 times the Tourette’s risk¹²⁶
• 9.91 times the risk of epilepsy¹²⁷
• 8.14 times the risk of mental retardation / intellectual development disorder¹²⁸
• 7.2-fold ASS risk¹²⁹
• 3.05 times the risk of ADHD¹²³
• Depression:
  • 2.01-fold risk of depression¹³⁰
  • no significantly increased risk of schizophrenia¹²³
• no significantly increased risk of schizophrenia¹²³

1.26. ANKRD17, Ankyrin Repeat Domain Containing 17¶

Other names: Ankyrin Repeat Domain 17; GTAR; KIAA0697; NY-BR-16; MASK2; Serologically Defined Breast Cancer Antigen NY-BR-16; Ankyrin Repeat Domain-Containing Protein 17; Gene Trap Ankyrin Repeat Protein; FLJ22206; CAGS
So far, 33 people with ADHD have been identified worldwide.¹³¹

ANKRD17 is associated with:

• ANKRD17-related neurodevelopmental syndrome¹³²
  • Developmental delays, especially in speech
  • characterized by variable mental disability
  • Further features:
    • ASS
    • ADHD
    • ophthalmological anomalies (strabismus, refractive errors)
    • Growth disorders
    • Nutritional difficulties
    • recurrent infections
    • Gait and/or balance disorders
    • Epilepsy
  • Characteristic craniofacial features:
    • triangular face shape
    • high front hairline
    • deep-set and/or almond-shaped eyes with periorbital fullness
    • low-set ears
    • thick nostrils
    • flared nostrils
    • full cheeks
    • thin vermilion (vermilion) on the upper lip
    • rarer
      • Cleft palate with Pierre Robin sequence
      • Renal agenesis
      • Scoliosis.
• Chopra-Amiel-Gordon syndrome
• non-specific syndromic intellectual disabilities
• KBG syndrome
  • KBG is a rare syndrome. Genetic variants in ankyrin repeat domain 17 (ANKRD17), ANKDR 11 and deletions in 16q24.3 can cause KBG syndrome.
  • More on KBG syndrome under ANKRD11, Ankyrin Repeat Domain Containing 11

1.27. KMT2B, lysine methyltransferase 2B¶

Other names: MLL2; TRX2; HRX2; WBP7; MLL4; Histone-Lysine N-Methyltransferase 2B; KIAA0304; CXXC10; MLL1B; Myeloid/Lymphoid Or Mixed-Lineage Leukemia (Trithorax Homolog, Drosophila) 4; Myeloid/Lymphoid Or Mixed-Lineage Leukemia Protein 4; Lysine (K)-Specific Methyltransferase 2B; WBP-7; Histone-Lysine N-Methyltransferase MLL4; Mixed Lineage Leukemia Gene Homolog; Lysine N-Methyltransferase 2B; WW Domain Binding Protein 7; WW Domain-Binding Protein 7; Trithorax Homologue 2; Trithorax Homolog 2; EC 2.1.1.364; DYT28; MRD68

The KMT2B protein contains several domains, including a CXXC zinc finger, three PHD zinc fingers, two FY-rich domains and a SET domain (Suppressor of Variegation, Enhancer of Zeste, and Trithorax). The SET domain is a conserved C-terminal domain that is characteristic for proteins of the MLL (mixed-lineage leukemia) family. The KMT2B gene is ubiquitously expressed in adult tissues. It is also amplified in solid tumor cell lines.
KMT2B is a histone methyltransferase that catalyzes the methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of “Lys-4” of histone H3 (H3K4) via a non-processive mechanism. As part of the chromatin remodeling machinery, it predominantly forms H3K4me1 and H3K4me2 methylation marks at active chromatin sites where transcription and DNA repair occur. KMT2B likely plays a redundant role with KMT2C in the accumulation of H3K4me1 marks on primed and active enhancer elements. KMT2B plays a central role in the regulation of beta-globin locus transcription by being recruited by NFE2. KMT2B plays an important role in controlling the amount of H3K4me during oocyte growth and pre-implantation development. KMT2B is required during the transcriptionally active period of oocyte growth for the establishment and/or maintenance of H3K4 trimethylation (H3K4me3), the global transcriptional silencing that precedes resumption of meiosis, oocyte survival and normal activation of the zygotic genome.¹³³
KMT2B is associated with

• intellectual development disorder, autosomal dominant 68
• Tumor (possibly)
• Dystonia 28, onset in childhood
  KMT2B-Related Dystonia is associated with ADHD Symptoms.¹³⁴
  • Gene variants that can trigger the so-called “KMT2B-Related Dystonia” are:
    • heterozygous pathogenic variant in KMT2B or
    • heterozygous interstitial deletion of 19q13.12, which includes a KMTB2 whole gene deletion
  • KMT2B-Related Dystonia is a very rare Disorder. To date, 39 people with ADHD are known.
  • Onset of dystonia usually within the first ten years of life, but can also occur in the second decade or later
  • First appearance:
    • Mostly dystonia of the lower limbs, manifested as:
      • Toe walk
      • abnormal gait
      • Balance disorders
    • Rarer:
      • Dystonia of the upper limbs
      • cervical or truncal dystonia
  • With increasing age:
    • pronounced cervical, laryngeal and/or cranial dystonia, manifested as
      • Retrocollis
      • Torticollis
      • Dysarthria/Anarthria
      • Dysphonia
      • Difficulty swallowing and chewing
  • Within two to 11 years after onset: development into generalized dystonia
  • KMT2B-Related Dystonia is associated with ADHD symptoms.

Related signal paths:

• PKMTs methylate histone lysines
• Gene expression (transcription)
• DNA-binding transcription factor activity
• Histone methyltransferase activity (H3-K4-specific)

Paralog: KMT2A

KMT2B-Related Dystonia is associated with ADHD symptoms.¹³⁴¹³⁵

1.28. H1-4, Rahman syndrome¶

Other names: H1.4 Linker Histone, Cluster Member; HIST1H1E; H1s-4; H1.4; H1F4; Histone Cluster 1 H1 Family Member E; H1 Histone Family, Member 4; Histone Cluster 1, H1e; Histone 1, H1e; Histone H1s-4; Histone H1.4; Histone H1b; H1e; DJ221C16.5; RMNS; H1E

H1-4 encodes a protein. The histone H1 protein binds to the linker DNA between the nucleosomes and forms the chromatin fiber. Histone H1 is necessary for the condensation of nucleosome chains into more highly structured fibers. It also acts as a regulator of individual gene transcription through chromatin remodeling, nucleosome spacing and DNA methylation.¹³⁶

H1-4 is associated with

• Hist1h1e syndrome (Rahman syndrome)¹³⁷
  • Mental disability (mild to severe) (100 %)
  • Abnormal brain MRI (92%)
    • in particular anomalies of the corpus callosus
  • Cryptorchidism (75 %)
  • Hypotension (67 %)
  • Behavioral problems (59 %)
    • Anxiety, phobias
    • compulsive behavior
    • ADHD
    • Aggression
    • auditory hypersensitivity
    • ASS symptoms
  • Skeletal features (54 %)
  • Abnormal dentition (51 %)
    • Crumbling teeth
    • missing teeth
    • multiple caries
  • Congenital cardiac anomalies / Abnormal echocardiogram (40 %)
    • Atrial septal defect most common
  • Hypothyroidism (29 %)
  • delayed motor development

Related signal paths:

• cellular reactions to stimuli
• programmed cell death

Paralog: H1-5

1.29. SATB2¶

SATB2-associated syndrome (SAS) is a multisystem disorder with developmental delay or mental retardation.
Causes: de novo occurrence of:¹³⁸

• heterozygous intragenic pathogenic SATB2 variant
• heterozygous non-recurrent deletion at 2q33.1, which includes SATB2
• Chromosome translocation or inversion with a 2q33.1 breakpoint that disrupts SATB2
• chromosomal duplication with breakpoints that include SATB2.

Symptoms:¹³⁸

• Speech delay and/or lack of speech (in all people with ADHD)
• jovial or friendly personality
• autistic tendencies
  - Restlessness or aggressive outbursts
• Self-harm
  - Impulsiveness
  - Hyperactivity
• States of anxiety
• Difficulty falling asleep and staying asleep
• sensory problems
• Hypotension (in most people with ADHD)
• EEG abnormalities (frequent)
• clinical seizures (20% of people with ADHD)
• Status epilepticus during sleep
• non-specific dysmorphic features
• Palate anomalies (cleft palate, high arched palate, laryngeal insufficiency, bifid uvula)
• Dental anomalies (including abnormal shape or size of the upper central incisors, tooth protrusion, hypodontia and delayed tooth eruption)
• Skeletal anomalies (scoliosis, curvature of the tibia and joint contractures)
• Bone fractures (one in three)
• low bone mineral density (one in four)
• pre- and postnatal growth disorders
• Nutritional problems
• Eye anomalies (strabismus, refractive errors)
• cardiovascular, genitourinary and ectodermal findings

1.30. ODC1, ornithine decarboxylase 1, Bachmann-Bupp syndrome, BABS¶

Other names: ODC; Ornithine decarboxylase; EC 4.1.1.17; NEDBIA; NEDBA; BABS

The enzyme ODC1 catalyzes the first and rate-limiting step of polyamine biosynthesis, which converts ornithine to putrescine, which is the precursor for the polyamines spermidine and spermine. Polyamines are essential for cell proliferation and play a role in cellular processes ranging from DNA replication to apoptosis. The activity level of the ODC1 enzyme varies in response to growth-promoting stimuli and has a high turnover rate compared to other mammalian proteins. Originally, the gene encoding this enzyme was localized on both chromosome 2 and chromosome 7. It has since been found to be localized on 2p25, with a pseudogene located on 7q31-qter.¹³⁹
ODC1 is associated with:

• Sleeping sickness
• Bachmann-Bupp syndrome
  • Bachmann-Bupp syndrome (BABS) is characterized by¹⁴⁰
    • pronounced alopecia (hair loss)
    • global developmental delay in the moderate to severe range
    • Hypotension
    • non-specific dysmorphic features
    • Behavioral problems
      • ASS
        - ADHD
    • Feeding problems
    • Hair
      • pronounced alopecia (hairlessness)
      • usually present at birth
      • can be sparse
      • may have unexpected color
      • falls out in large clusters in the first weeks of life
    • Seizures at the beginning of later childhood (rare)
    • Conductive hearing loss (rare)

Abnormal metabolites of polyamine metabolism (including elevated levels of N-acetylputrescine) are indicative of BABS.
Diagnosis by molecular genetic testing for heterozygous pathogenic de novo variants of the ODC1 gene.

Related signaling pathways:

• L-methionine salvage cycle III
• Regulation of activated PAK-2p34 by proteasome-mediated degradation
• Protein homodimerization activity
• Ornithine decarboxylase activity

Paralog: AZIN2

1.31. CYP27A1, cerebrotendinous xanthomatosis, CTX¶

Cerebrotendinous xanthomatosis is a rare genetic disorder (prevalence 1:70,000) of the CYP27A1 gene that is inherited in an autosomal recessive manner. CTX is often only diagnosed in early adulthood due to the neurological symptoms that then become apparent.¹⁴¹
CTX includes:¹⁴²

• Lipid storage impaired
• Bile acid biosynthesis pathways altered
• Cholesterol metabolites (e.g. cholestanol) increased in
  • Fabric
  • Brain
  • Eye lens
  • Tendons

Symptoms:¹⁴²

• progressive neurological problems (64-92%)
  • Spasticity
  • Pyramidal signs
• neuropsychiatric symptoms
  • cognitive impairments (87 %)
  • Behavioral disorders
• juvenile cataracts (82 %)
• Xanthomas (yellowish / orange fat deposits)
  • Tendon xanthomas (76 %)
• Osteoporosis (65 %)
• chronic diarrhea (31 %)
• psychiatric disorders (11.4%)
• Cardiovascular diseases

Cerebrotendinous xanthomatosis may be associated with ADHD symptoms.¹⁴³¹⁴²

1.32. SMAD4, Myhre¶

Other names: SMAD Family Member 4; DPC4; MADH4; Mothers Against Decapentaplegic Homolog 4; Deletion Target In Pancreatic Carcinoma 4; MAD Homolog 4; MAD, Mothers Against Decapentaplegic Homolog 4 (Drosophila); Mothers Against Decapentaplegic, Drosophila, Homolog Of, 4; SMAD, Mothers Against DPP Homolog 4 (Drosophila); Deleted In Pancreatic Carcinoma Locus 4; SMAD, Mothers Against DPP Homolog 4; Mothers Against DPP Homolog 4; SMAD 4; HSMAD4; MYHRS; Smad4; JIP¹⁴⁴

Associated with:

• Myhre syndrome
  • Since its discovery in 1981, only 300 cases of Myhre have been detected worldwide¹⁴⁵
• juvenile polyposis syndrome

Connected signal paths:

• Autolysis of the E3 ubiquitin ligase COP1
• Gene expression (transcription)
• DNA-binding transcription factor activity
• sequence-specific DNA binding

Paralog: SMAD2

Myhre is associated with an increased prevalence of ADHD and ASD.¹⁴⁵

Symptoms of Myhre syndrome:¹⁴⁵

• Joint stiffness
• restrictive lung and cardiovascular diseases
• progressive and proliferative fibrosis
• Skin thickening
• recurrent infections (including otitis media, sinusitis, mastoiditis, croup)
• Hearing loss (progressive)
• Growth impaired early on
• Obesity in adolescence
• Refractive error
• Astigmatism
• Correctopia
• Abnormalities of the optic nerve
• gastroesophageal reflux disease
• Constipation
• Encopresis
• Stenosis of the GI tract (less common)
• Hirschsprung’s disease (less common)
  • Hirschsprung’s disease is probably associated with an increased prevalence of ADHD¹⁴⁶
• metabolic dysfunction of the liver (less common)

Traumas can be triggering:¹⁴⁵

• abnormal scarring
• Adhesions
• invasive medical interventions / operations
• Effusions in the heart, airways, lungs, uterus or peritoneum, which can develop into fibrosis

Characteristic facial features in most people with ADHD:¹⁴⁵

• short palpebral fissures
• deep-set eyes
• Underdevelopment of the upper jaw
• short philtrum
• thin upper lip
• narrow mouth
• Prognathy

Neurological symptoms:¹⁴⁵

• Developmental delays (usually mild to moderate)
• cognitive impairments (usually mild to moderate)
• ASS
• ADHD
• Fear

1.33. SETD5¶

Cause pathogenic gene variants of SETD5:¹⁴⁷

• Hypotension (39.2 %)
• hyperkinetic movement disorders including stereotypies and chorea (21.4%)
• Gait disorders (35.7 %)
  • Toe walking
  • unsteady gait
  • Changes in fine motor skills
• Epilepsy (14 %)
  • epileptic spasms
  • focal motor and non-motor seizures
• mild to severe intellectual disability or global developmental delay (75%)
• borderline intellectual capacity (21.4 %)
• ASS
• ADHD
• psychotic disorders
• other internalizing and externalizing symptoms

1.34. RUNX1T1¶

Runt-related transcription factor 1 translocated to 1 (RUNX1T1; also known as Eight-Twenty-One [ETO]) encodes a transcriptional regulator for hematopoietic genes and is known to be involved in hematologic malignancies, particularly acute myeloid leukemia (AML).
RUNX1T1 de novo changes:¹⁴⁸

• craniofacial dysmorphia
• neurological developmental disorders, including
  • Developmental delays
  • Learning disorders
  • ADHD
  • ASS

1.35. ARID1B haploinsufficiency¶

ARID1B haploinsufficiency is estimated to occur in 1 in 10,000 to 1 in 100,000 people (0.01 to 0.001% of the population).¹⁴⁹

ARID1B-related disorder (ARID1B-RD) represents a clinical continuum. It ranges from classic Coffin-Siris syndrome to mental retardation with or without non-specific dysmorphic features:¹⁵⁰

• Aplasia or hypoplasia of the distal phalanx or nail of the fifth and other fingers
• Developmental or cognitive delays of varying degrees
• characteristic facial features
• Hypotension
• Hypertrichosis
• sparse scalp hair
• Developmental delays
  • Language development often stronger than motor development)
  • Malformations of the heart
  • Malformations of the gastrointestinal tract
  • Malformations of the urogenital system
  • Malformations of the central nervous system
• Nutritional difficulties
• slow growth
• ophthalmologic anomalies
• Hearing impairments
• Seizures
• ADHD
• ASS

1.36. Congenital disorder of glycosylation, CDG¶

To date, there have only been a few cases in which abnormal glycosylation (congenital disorder of glycosylation, CDG) has been associated with ADHD:¹⁵¹

• Alpha-1,3-glucosyltransferase (ALG8) CDG shows musculoskeletal, dermatologic and cardiac symptoms as well as mental retardation¹⁵²
• People with ADHD showed
• increased biantennary glycans with antenna fucose (A2FG2) and decreased tri- and tetra-antennary glycans.¹⁵³¹⁵⁴
• reduced α2-3 sialylation¹⁵⁴
• A single case with conserved oligomeric Golgi (COG-) CDG showed ADHD.¹⁵⁵

CDG has already been described in other neurodevelopmental disorders such as autism.
Other N-glycosylation abnormalities have been described in ADHD. The following were found in people with ADHD

A connection was also found with ASD, ataxia and other disorders that occur more frequently with ADHD,¹⁵⁶

A lack of N-linked glycosylation can impair the membrane localization of the D5R (but not the D1R)¹⁵⁷. The D5R plays a role in ADHD.
Conflicting glycosylation of the dopamine transporter (DAT) leads to more efficient transport of dopamine (which is the classic pathway for ADHD) and is discussed as a possible pathway for midbrain dopamine cell vulnerability in Parkinson’s disease.¹⁵⁸

1.36.1. Transferrin, TF¶

A case study reports on a young woman with a heterozygous transferrin mutation c.1295 A > G, which destroys the glycosylation site on asparagine 432. This means that the transferrin of the person with ADHD only has a single glycosylation site, and hypoglycosylation is not indicative of CDG disease. ADHD was present.¹⁵¹ MPH led to side effects, while lisdexamfetamine relieved ADHD symptoms without side effects. The case study suggests a monogenetic causative possibility due to transferrin mutations for ADHD.

1.36.2. STT3A, STT3 Oligosaccharyltransferase Complex Catalytic Subunit A¶

Other names: STT3-A, TMC, Integral Membrane Protein 1, ITM1, Dolichyl-Diphosphooligosaccharide-Protein Glycosyltransferase Subunit STT3A, STT3A, Catalytic Subunit Of The Oligosaccharyltransferase Complex, Dolichyl-Diphosphooligosaccharide Protein Glycotransferase, Oligosaccharyl Transferase Subunit STT3A, Transmembrane Protein TMC

The protein STT3A is a catalytic subunit of the N-oligosaccharyltransferase (OST) complex, which transfers glycan chains to asparagine residues of target proteins in the endoplasmic reticulum. It is associated with CFTR activation by S-nitrosoglutathione (normal and CF) and the translation of structural proteins.
STT3A is associated with

• congenital disorder of glycosylation, type Iw, autosomal recessive
• congenital disorder of glycosylation, type Iw, autosomal dominant

In view of the influence of STT3A on N-glycolysis, we assume that the pathway of action on the dopaminergic system is comparable to that of 1.105. MAN2A2.

One study found STT3A to be one of the 51 most likely gene candidates for ADHD.⁴⁸

Autosomal dominant congenital glycosylation disorder (CDG) type Iw (OMIM# 619714) Is caused by a heterozygous mutation in the STT3A gene. Most CDGs are inherited in an autosomal recessive (AR) manner, but several cases with an autosomal dominant (AD) form of AR-CDG have recently been identified.
A case study describes a 17-year-old male with macrocephaly, failure to thrive, short stature, epilepsy, ASD, ADHD, mild developmental delay, intermittent hypotonia, dysmorphic features, and a slightly enlarged aortic root with a previously unreported de novo STT3A variant (c.1631A > G: p.Asn544Ser). This variant removes a glycosylation site and was predicted to be destabilizing by structural biology modeling. The metabolomic profile indicates an abnormal CDG type Iw transferrin profile. Phenotypic, molecular and metabolic findings were consistent with CDG type Iw due to a heterozygous STT3A variant.¹⁵⁹

1.36.3. COG6¶

Two Swedish cases of congenital glycosylation disorders of the conserved oligomeric Golgi complex subunit 6 (COG6-CDG) are known.
One of them was diagnosed with ADHD at the age of 4 years and 9 months. The other was not (yet) diagnosed with ADHD at the age of 3.5 years.
Other clinical symptoms included mental retardation, delayed myelination of the brain, progressive microcephaly, joint laxity, hyperkeratosis, frequent infections and tooth enamel hypoplasia. Compound heterozygous variants in COG6 were identified in one family: c.785A>G; p.Tyr262Cys and c.238G>A; p.Glu80Lys. In addition, a previously undescribed homozygous duplication (c.1793_1795dup) was considered to be the cause of the disease. The cells of persons with ADHD show significantly slower anterograde and retrograde ER-Golgi transport.¹⁵⁵

1.37. PTS-related tetrahydrobiopterin deficiency, PTPSD¶

The exact prevalence of PTPSD is unknown.
A prevalence of 1:75,000 to 1:150,000 is assumed for all forms of BH4 deficiency. PTPSD accounts for around 54% of all BH4 deficiency states, meaning that a PTPSD prevalence of 1:150,000 to 1:300,000 can be assumed¹⁶⁰

PTS-related tetrahydrobiopterin deficiency (PTPSD) is a monogenetic disorder.
Tetrahydropterin is an important cofactor for the synthesis of phenylalanine hydroxylase (PAH), tyrosine hydroxylase and tryptophan hydroxylase.

PTPSD is inherited in an autosomal recessive manner¹⁶⁰
If both parents are known to be heterozygous for a pathogenic PTS variant, each sibling of a person with ADHD has a probability at conception of

• 25 % to also be affected
• 50% to be an asymptomatic carrier
• 25% not to inherit any of the familial pathogenic PTS variants

If one parent has PTPSD and one parent has two normal PTS alleles, the children are obligate heterozygotes. If the mother is the person with ADHD, MPKU syndrome is a critical factor.¹⁶⁰

PTPSD is associated with an increased risk of ADHD.¹⁶⁰ The prevalence of ADHD is unknown.

1.38. Glucose-6-phosphate dehydrogenase deficiency (G6PD)¶

Glucose-6-phosphate dehydrogenase (G6PD) deficiency increased the risk of ADHD by 16%¹⁶¹

G6PD deficiency is the most common enzyme deficiency worldwide. It results from an X-linked genetic disorder and affects around 4.9% of all people. As G6PD deficiency offers a certain degree of protection against malaria, it is geographically more common in areas where malaria occurs. The prevalence in Germany is less than 1%.
The enzyme glucose-6-phosphate dehydrogenase (G6PD) facilitates the synthesis of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), which are involved in oxidation-reduction equilibrium regulation. G6PD deficiency causes reduced GSH levels and thus increased oxidative stress.

Defect variants:¹⁶²

• Defect variant A
  • G6PD residual activity of 5 to 15 % of the standard
  • Common in Southern Europe, West Africa, African-American population in the USA
• Mediterranean defect variant
  • G6PD residual activity below 1 % of the standard
  • Common in Mediterranean coastal areas, Middle East, India
• G6PD Vianchan and G6PD Mahidol: Southeast Asia
• G6PD Canton: China
• G6PD Union: Worldwide

G6PD deficiency is mostly food-related (favism; hemolytic reaction to the consumption of fava beans) and sometimes genetic (more common in the Mediterranean region and the Middle East, partly in Asia and Africa).
G6PD deficiency can trigger (especially in children):

• severe hemolysis
• Hyperbilirubinemia
• Jaundice
• Hearing disorders
• Behavioral disorders
• long-lasting neurological damage
• increased production of reactive oxygen species (ROS)
  • resulting in activation of astrocytes and microglia, increased proinflammatory chemokines and cytokines, neuroinflammation, impaired brain development
• Imbalance in the antioxidant system
  • this leads to impairment of astrocytes, neuronal death and DNA damage
  • oxidative cell death of leukocytes, myocytes and other immunological players.

1.39. Creatine deficit disorders¶

Creatine deficiency disorders are rare monogenetic disorders. At present, 130 people with ADHD are known worldwide.
Genetic counseling.
Creatine deficiency disorders can be caused by¹⁶³

• GAMT deficiency due to a pathogenic variant of the GAMT gene, autosomal recessive inheritance
• AGAT deficiency due to a pathogenic variant of the GATM gene, autosomal recessive inheritance
• CRTR deficiency due to a pathogenic variant of the SLC6A8 gene, X-linked inheritance

Creatine-deficiency disorders are associated with an increased risk of ADHD.¹⁶³

1.40. Argininosuccinate lyase deficiency (ASLD)¶

Argininosuccinate lyase deficiency (ASLD, argininosuccinic acid disease) is an inborn error of urea synthesis. ASLD can occur as a neonatal or late-onset disease.
Monogenetic disorder caused by mutations in the ASL gene. Inherited in an autosomal recessive manner (both parents must be carriers of a mutated gene for the child to be affected).
Prevalence: 1 to 9 / 100 000¹⁶⁴

In addition to ASLD, there are other forms of urea cycle disorders: Ornithine transcarbamylase deficiency (OTCD), carbamoyl phosphate synthetase 1 deficiency (CPS1D); argininosuccinate synthetase deficiency (ASSD), arginase 1 deficiency (ARG1D). An increased prevalence of ADHD was found in particular with ASSD¹⁶⁵

Neonatal ASLD:¹⁶⁶

• Hyperammonemia within the first few days after birth
  • Symptoms: increasing vomiting, lethargy, refusal to eat, tachypnea and respiratory alkalosis
  • in the absence of treatment, worsening of lethargy, seizures, coma, even death

Late onset ASLD:¹⁶⁶

• episodic hyperammonemia triggered by acute infections or stress
• with and without documented episodes of hyperammonemia:
  • cognitive impairments
  • Behavioral problems
  • Learning disorders

Long-term symptoms of ASLD

• Acute hyperammonemia and associated complications
• neurological and neurocognitive characteristics
  • ADHD
    • Attention problems in 50% of people with ADHD¹⁶⁷
    • ASLD impairs tyrosine hydroxylase in the nucleus coeruleus¹⁶⁷
  • intellectual and developmental disabilities
  • Learning disorders
  • Developmental delay in 92% of people with ADHD¹⁶⁸
• Seizures
• Motor and coordination abnormalities
• Liver diseases
  • Hepatomegaly
  • Hepatitis
  • Steatosis
  • Fibrosis
  • Cirrhosis
• Trichorrhexis nodosa (coarse, brittle hair that breaks easily)
• systemic hypertension
• Hypokalemia

2. Monogenetic animal models for ADHD symptoms¶

Animal models are used to investigate the effects of individual deactivated or overexpressed genes. Since in the vast majority of cases only a single gene is altered, the effects of this single gene can be easily determined by comparison with the same mouse strain without gene alteration.
Cabana-Domínguez et al have compiled an overview of 161 mouse models in which the manipulation of individual genes triggered hyperactivity, hyper- and hypoactivity, impulsivity or inattention.¹⁶⁹

2.1. Monogenetic causes of hyperactivity¶

Cabana-Domínguez et al found 146 mouse models in which the manipulation of the following genes triggered hyperactivity.¹⁶⁹ Further mouse models are included with individual source names.

• ABCA2
• ABCG1
• ACTL6B
• ADCY3
• ADCYAP1
• ADIPOR2
• ANKFN1
• ANKS1B
• AP3B2
• AP3B2
• AP3D1
• APAF1
• APP
• ARRDC3
• ARSA
• ATF2
• ATP1A3
• ATRN
• BDNF
• CACNA2D3
• CACNA2D4
• CACNG2
• CADM1
• CALM1
• CAMK2A
• CDH23
• CDK17
• CDK5R1
• CDKL5
• CELF4
• CHD3
• CHD7
• CHRD
• CHRM1
• CHRM4
• CIC
• CKAP5
• CLIC5
• CNTNAP2
• CREBBP
• DGAT1
• DGKB
• DISC1
• DNAJB5
• DRD1
• DRD2
• DRD3
• DTNBP1
• DUSP18
• EEF1B2
• ELMOD3
• EN2
• EPS15L1
• ESPN
• ESR1
• FMR1
• FOS
• FOXI1
• FXR2
• GABRA1
• GABRA3
• GABRB3
• GIT1
• GLRA1
• GNAI2
• GNAO1
• GPR135
• GPR88
• GRIA1
• GRID2
• GRIN2B
• HMOX1
• HTR2C
• HTT
• IGSF9B
• IL6
• INTS3
• KCNA4
• KCNE1
• KPNA4¹⁷⁰
  • But not KPNA3¹⁷⁰
• LDLR
• LMX1A
• LRRK2
• MAGI2
• MAOB
• MAPK3
• MAPT
• MCOLN3
• MYO6
• MYO7A
• NCOR1
• NLGN2
• NLGN3
• NOX3
• NPAS3
• NPC1
• NR4A2
• NR4A3
• NUP153
• OPRD1
• OTC
• OTOG
• PER1
• PITX3
• PKD2L2
• PNPLA6
• POU4F3
• PPARGC1A
• PPFIA3
• PPM1F
• PTCHD1
• PTPRK
• RAB5B
• RGS4
• RNF214
• RTL10
• RXYLT1
• SCN1A
• SHANK2 (see above)
• SHANK3
• SIRT1
• SLC12A6
• SLC1A2
• SLC26A10
• SLC5A7
• SLC6A3
• SLC9A6
• SNAI2
• SNCA
• SOBP
• SYNGAP1
• SYT4
• TBC1D8
• TBX10
• TECPR2
• TIP
• TMIE
• UBA6
• USH1C
• USH1G
• VIM
• VLDLR
• WDR41
• WHRN
• ZBTB20
• ZEB1
• ZPLD1

2.2. Monogenetic causes of hyperactivity and hypoactivity¶

Cabana-Domínguez et al found 6 mouse models in which manipulation of the following genes induced hyperactivity and hypoactivity:¹⁶⁹

• GPX6
• HTT
• LEPR
• PSAP
• SHANK3
• SLC6A8

2.3. Monogenetic causes of impulsivity¶

Cabana-Domínguez et al found 4 mouse models in which manipulation of the following genes induced impulsivity:¹⁶⁹

• CADM1
• COMT
• PER1
• SHANK3

2.4. Monogenetic causes of attention problems¶

Cabana-Domínguez et al found 5 mouse models in which manipulation of the following genes induced inattention:¹⁶⁹

• COMT
• PSEN1 (lack of attention maintenance)
• PTCHD1
• SNAP25
• TARDBP (executive dysfunction)

3. Chromosomal aberrations as causes of ADHD¶

Chromosomal aberrations affect several or all genes of the chromosome and are therefore not a monogenetic cause. However, they are a monocausal genetic cause, which is why we include them in this context.

3.1. Sex chromosome aneuploidy: 48,XXY; 48,XXX; 48,XYY and 48,XXYY (up to 72%)¶

Rare sex chromosome aneuploidy (SCA) disorder
Prevalence 48,XXYY: 1 in 18,000 to 40,000 male newborns¹⁷¹

Symptoms:

• tall stature (average height over 1.90 m)
• hypergonadotropic hypogonadism (testosterone deficiency)
• Infertility
• Developmental delays
• Learning disorders
• mental impairments

Common accompanying behavioral problems are

• ADHD (72%; for comparison: 36% for XXY, 52% for XXX and 76% for XYY)¹⁷²¹⁷³
• States of anxiety
• Depression
• Sleep disorders
• Irritability
• aggressive behavior

One study found:¹⁷¹
71% (of 101, 4.5 to 38 years) received psychotropic drugs, most commonly ADHD stimulants (78.9%, first medication success rate 43.9%), anti-anxiety/antidepressant medications (60.6%, first medication success rate 84.2%). Subsequent trials with medications of the same class improved the success rates per person in all medication classes except for sleep and mood stabilizers.

Assuming an ADHD prevalence of 50% across all variants and an aneuploidy prevalence of 1 in 30,000, this could explain one in 60,000 cases of ADHD in males. With an ADHD prevalence of 5 %

3.2. Klinefelter syndrome (47,XXY) (25 % to 63 %)¶

The prevalence of Klinefelter in boys is 1 in 500 to 1 in 1,000. Only about a quarter of people with ADHD are diagnosed, as the effects are often mild.

Klinefelter is associated with an ADHD prevalence of 25 % to 63 %.¹⁷⁴
Klinefelter syndrome is characterized by an additional X chromosome. 63 % of people with ADHD, 65 % speech disorders, 27 % ASD.¹⁷⁵.
Boys with Klinefelter without ADHD showed executive functions similar to those of boys with Klinefelter and ADHD. It appears that Klinefelter itself is associated with executive problems {{Tragantzopoulou P, Giannouli V (20
24): Understanding the Neuropsychological Implications of Klinefelter Syndrome in Pediatric Populations: Current Perspectives. Pediatr Rep. 2024 May 25;16(2):420-431. doi: 10.3390/pediatric16020036. PMID: 38921701; PMCID: PMC11206885.https://pmc.ncbi.nlm.nih.gov/articles/pmid/38921701/ REVIEW}}

Klinefelter is said to correlate with ADHD-I in particular.¹⁷⁴

3.3. Trisomy 21, Down syndrome (14.6 % to over 50 %)¶

The prevalence of Down syndrome is given as 1:750.

Down syndrome correlated with a 1.74-fold risk of ADHD (14.6% overall) and a 5.4-fold risk of ASD (6.38% overall).¹⁷⁶
In special institutions for children with Down syndrome, more than 50% are said to suffer from ADHD at the same time.¹⁷⁷
Down syndrome is also associated with an increased ASD prevalence of 39%¹⁷⁸

Mosaic Down syndrome is characterized by trisomy 21, which is not present in all cells. Among the persons with ADHD, 2.08 % were found to have mosaicism.¹⁷⁹
People with mosaicism were more likely than those not affected to show

• ADHD (+ 26.5 %; 17.7 % compared to 14.0 %)
• ASS (+ 44.8 %; 13.9 % compared to 9.6 %)

3.4. 22Q11.2 duplication syndrome (18.2 % to 44 %)¶

Other names: DUP22Q11.2; Chromosome 22q11.2 Microduplication Syndrome¹⁸⁰

The 22q11.2-duplication syndrome Occurs once in 1600 births.
22q11.2Dup is usually inherited from the parents.
The prevalence of ADHD at 22q11.2Dup is around 18.2% to 44%.¹⁸¹
Among persons with ADHD, a 22q11.2Dup was found in 0.25 to 0.33%.

Other typical symptoms are

• Facial abnormalities
• congenital heart defects
• Immunodeficiencies
• Cleft palate
• Short stature
• Obesity
• Developmental delay

ADHD symptoms are treated according to the usual regimens. A low starting dosage with slow up-dosing is also recommended here.

3.5. 22Q11.2 deletion syndrome (6 % to 37 %)¶

Other names: DEL22Q11.2; C22DELq11.2; C22DDELS¹⁸² CATCH 22, Cayler cardiofacial syndrome, Di-George syndrome, DiGeorge sequence, microdeletion 22q11.2, monosomy 22q11, Sedlackova syndrome, Sphrintzen syndrome, syndrome of conotruncal anomaly with facial dysmorphia, Takao syndrome

The prevalence of velocardiofacial syndrome is 1 to 5 / 10,000 (0.01 to 0.05 %)¹⁸³

The 22q11.2-deletion syndrome Occurs once in 2150 births, making it the most common deletion syndrome.
22q11.2Del usually develops de novo, i.e. not as an inheritance of genetic traits from the parents.
The prevalence of ADHD in 22q11.2Del is increased¹⁸⁴ and is around 6% to 37%.¹⁸¹¹⁸⁵ One study found ADHD in 2 out of 6 persons with ADHD.¹⁸⁶ People with 22q11.2 deletion syndrome (DS) have an increased risk of comorbid mental disorders such as ADHD, schizophrenia, depression or intellectual disability.¹⁸⁷ More than 85% of people with DEL22Q11.2 without an ADHD diagnosis reported ADHD symptoms.¹⁸⁸

Among people with ADHD, 0.14% were found to have 22q11.2Del.

DEL22Q11.2 is associated with

• Chromosome 22Q11.2 Deletion syndrome, distal
• Corneal staphyloma.

ADHD symptoms are treated according to the usual regimens. A low starting dosage with slow up-dosing is also recommended here.

3.6. Q11.23 deletion, Williams syndrome (64.7 % to 84 %)¶

Williams syndrome, or Williams-Beuren syndrome, occurs in 1 in 20,000 people and is caused by a microdeletion of around 2 million DNA base pairs from the q11.23 region of chromosome 7. This segment contains 24 genes, including the ELN gene (elastin gene), which is the main cause of the arterial stenosis that occurs in 50 % to 75 % of people with ADHD.¹⁸⁹ Williams syndrome is also common:

• Hypercalcemia at 15 %
• Hypercalciuria
• Arterial calcification
• Nephrocalcinosis
• Diabetes or prediabetic condition
• Subclinical hypothyroidism due to small thyroid gland
• Defects of the urogenital system in 20-35 %
  • Ectopic kidneys
  • Horseshoe kidney
  • Bladder diverticulum
• Hypotension
• Orthopaedic problems
  • Hyperflexibility of the joints (Ehlers Danlos)
    • Hyperreflective thighs
    • Bent knees
    • Spinal kyphosis
  • Lordosis
  • Scoliosis
• Simmband anomalies
  • Rough, tinny or hoarse voice¹⁹⁰
• Esophageal reflux at 25 %
• Intestinal diverticulum
• Chronic constipation at 50 %
• Chronic abdominal pain
  • Mostly due to increased anxiety symptoms
• ADHD with
  • 64.7 % of 16-year-olds¹⁹¹
  • Up to 84 %¹⁸⁹
  • MPH had an effect on 72.2 %¹⁹²
    • Good improvement in anxiety symptoms at the same time
    • With 2/3 sadness as a side effect
• Anxiety in the form of specific phobias at 43%¹⁸⁹ to 53.8%¹⁹¹
  • Especially with regard to certain noises¹⁹²
  • More generalized anxiety disorders with increasing age
• Hyperacusis at 84 %¹⁹³
• Mental disability
  • IQ on average 50 to 60 points (40 to 100)¹⁸⁹
  • Relative strengths:
    • Auditory memory
    • Certain language skills
    • Identification of objects and facial expressions
  • Relative weaknesses
    • Spatial memory
    • Mathematics
    • Spatial-motor skills such as orientation