Hyperreflexia, and Abnormality of skin pigmentation

• Global developmental delay
• Microcephaly
• Nystagmus
• Spasticity
• Tremor

SOURCES: OMIM MENDELIAN

Classical phenylketonuria is a severe form of phenylketonuria (PKU, see this term) an inborn error of amino acid metabolism characterized in untreated patients by severe intellectual deficit and neuropsychiatric complications.

CLASSIC PHENYLKETONURIA Is also known as classic pku

• Seizures
• Global developmental delay
• Microcephaly
• Growth delay
• Cataract

SOURCES: ORPHANET MENDELIAN

For a general discussion of xeroderma pigmentosum, see XPA (OMIM ), and of Cockayne syndrome, see CSA (OMIM ).Cleaver (1990) provided a review of the causes of xeroderma pigmentosum.

XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP B; XPB Is also known as xp, group b|xpbc

• Intellectual disability
• Short stature
• Hearing impairment
• Microcephaly
• Ataxia

SOURCES: MESH OMIM MENDELIAN

The disorders involving primarily the cerebellar parenchyma have been classified into six forms. In cerebelloparenchymal disorder III, cerebellar ataxia is congenital (non-progressive) and characterized by cerebellar symptoms such as incoordination of gait often associated with poor coordination of hands, speech and eye movements. The other features are congenital mental retardation and hypotonia, in addition to other neurological and non-neurological features. MRI or CT scan show marked atrophy of the vermis and hemispheres. A severe loss of granule cells with heterotopic Purkinje cells is observed. The mode of inheritance in the few reported families is autosomal recessive. In one family, cerebellar ataxia was associated to albinism.: In a large inbred Lebanese family the disease locus was assigned to a 12.1-cM interval on chromosome 9q34-qter between markers D9S67 and D9S312. The primary biochemical defect remains unknown. Up to now, the only treatment has consisted in early interventional therapies including intensive speech therapy and adequate stimulation and/or training.

AUTOSOMAL RECESSIVE CEREBELLOPARENCHYMAL DISORDER TYPE 3 Is also known as cpd iii|scar2|cpd3|cerebellar granular cell hypoplasia and mental retardation, congenital|autosomal recessive spinocerebellar ataxia type 2|cerebellar hypoplasia, nonprogressive norman type|cerebelloparenchymal disorder iii

• Intellectual disability
• Global developmental delay
• Short stature
• Generalized hypotonia
• Hearing impairment

SOURCES: OMIM MESH ORPHANET MENDELIAN

Autosomal recessive chorioretinopathy-microcephaly syndrome is a rare neuro-opthalmological disease characterized by severe microcephaly of prenatal onset (with diminutive anterior fontanelle and sutural ridging), growth retardation, global developmental delay and intellectual disability (ranging from mild to profound), dysmorphic features (sloping forehead, micro/retrognathia, prominent ears) and visual impairments (including microphthalmia to anophtalmia, generalized retinopathy or multiple punched-out retinal lesions, retinal folds with retinal detachment, optic nerve hypoplasia, strabismus, nystagmus). Brain MRI may show reduced cortical size, cerebral hemispheres, corpus callosum, pachygyria, symplified gyral folding or normal pattern. Other associated features include epilepsy and neurological deficits.

AUTOSOMAL RECESSIVE CHORIORETINOPATHY-MICROCEPHALY SYNDROME Is also known as autosomal recessive chorioretinopathy-microcephaly-intellectual disability syndrome

• Intellectual disability
• Seizures
• Global developmental delay
• Short stature
• Generalized hypotonia

SOURCES: ORPHANET OMIM MENDELIAN

Autosomal recessive spastic paraplegia type 23 (SPG23) is a rare, complex type of hereditary spastic paraplegia that presents in childhood with progressive spastic paraplegia, associated with peripheral neuropathy, skin pigment abnormalities (i.e. vitiligo, hyperpigmentation, diffuse lentigines), premature graying of hair, and characteristic facies (i.e. thin with ''sharp'' features). The SPG23 phenotype has been mapped to a locus on chromosome 1q24-q32.

AUTOSOMAL RECESSIVE SPASTIC PARAPLEGIA TYPE 23 Is also known as spastic paraparesis-vitiligo-premature graying-characteristic facies syndrome|lison syndrome|spg23|spastic paraparesis, vitiligo, premature graying, characteristic facies|spastic paraplegia with pigmentary abnormalities

• Seizures
• Short stature
• Microcephaly
• Ataxia
• Micrognathia

SOURCES: ORPHANET OMIM MESH MENDELIAN

Hartnup disease is a rare metabolic disorder belonging to the neutral aminoacidurias and characterized by abnormal renal and gastrointestinal transport of neutral amino acids (tryptophan, alanine, asparagine, glutamine, histidine, isoleucine, leucine, phenylalanine, serine, threonine, tyrosine and valine).

HARTNUP DISEASE Is also known as aminoaciduria, hartnup type|hartnup disease|hartnup disorder

• Intellectual disability
• Seizures
• Global developmental delay
• Short stature
• Generalized hypotonia

SOURCES: OMIM MESH ORPHANET MENDELIAN

Salt and pepper developmental regression syndrome, also known as Amish infantile epilepsy syndrome, is an autosomal recessive neurocutaneous disorder characterized by infantile onset of refractory and recurrent seizures associated with profoundly delayed psychomotor development and/or developmental regression as well as abnormal movements and visual loss (summary by Fragaki et al., 2013). Affected individuals develop hypo- or hyperpigmented skin macules on the trunk, face, and extremities in early childhood (summary by Boccuto et al., 2014). Not all patients have overt seizures (Lee et al., 2016).

AMISH INFANTILE EPILEPSY SYNDROME Is also known as epilepsy syndrome, infantile-onset symptomatic|infantile-onset symptomatic epilepsy syndrome-developmental stagnation-blindness syndrome|gm3 synthase deficiency|salt and pepper mental retardation syndrome|amish infantile epilepsy syndrome

• Intellectual disability
• Seizures
• Global developmental delay
• Generalized hypotonia
• Hearing impairment

SOURCES: OMIM ORPHANET MENDELIAN

Aniridia-cerebellar ataxia-intellectual disability syndrome, also known as Gillespie syndrome, is a rare, congenital, neurological disorder characterized by the association of partial bilateral aniridia with non-progressive cerebellar ataxia, and intellectual disability.

ANIRIDIA-CEREBELLAR ATAXIA-INTELLECTUAL DISABILITY SYNDROME Is also known as gillespie syndrome|aniridia, cerebellar ataxia, and mental retardation

• Intellectual disability
• Global developmental delay
• Generalized hypotonia
• Ataxia
• Nystagmus

SOURCES: MESH OMIM ORPHANET MENDELIAN

Neurodegeneration with brain iron accumulation is a genetically heterogeneous disorder characterized by progressive iron accumulation in the basal ganglia and other regions of the brain, resulting in extrapyramidal movements, such as parkinsonism and dystonia. Age at onset, severity, and cognitive involvement are variable (review by Gregory et al., 2009).Panthothenate kinase-associated neurodegeneration has been classified clinically as 'classic,' 'atypical,' or 'intermediate.' In the classic form, patients present within the first decade of life with rapidly progressing disease and loss of ambulation approximately 15 years later. In the atypical form, patients have onset in the second decade with slow progression and maintain independent ambulation after 15 years. In the intermediate form, patients have early onset and slow progression or later onset and rapid progression. Patients with early onset tend to develop pigmentary retinopathy, whereas those with later onset tend to have speech disorders and psychiatric features. All patients have the 'eye of the tiger' sign on brain MRI (Hayflick et al., 2003; Pellecchia et al., 2005).Kumar et al. (2006) noted that the 'eye of the tiger' sign is not pathognomonic for PANK2 mutations. They reported 2 unrelated adult patients with cognitive dysfunction who had the characteristic sign on MRI but did not have mutations in the PANK2 gene.Gregory et al. (2009) provided a detailed review of the different forms of neurodegeneration with brain iron accumulation.In addition, some patients with Kufor-Rakeb syndrome (OMIM ), also known as Parkinson disease-9 (PARK9), have iron deposition in the basal ganglia. Genetic Heterogeneity of Neurodegeneration with Brain Iron AccumulationNeurodegeneration with brain iron accumulation is an umbrella term that encompasses a group of genetically heterogeneous disorders. See also NBIA2A (OMIM ) and NBIA2B (OMIM ), both caused by mutation in the PLA2G6 gene (OMIM ); NBIA3 (OMIM ), caused by mutation in the FTL gene (OMIM ); NBIA4 (OMIM ), caused by mutation in the C19ORF12 gene (OMIM ); NBIA5 (OMIM ), caused by mutation in the WDR45 gene (OMIM ); NBIA6 (OMIM ), caused by mutation in the COASY gene (OMIM ); NBIA7 (OMIM ), caused by mutation in the REPS1 gene (OMIM ); and NBIA8 (OMIM ), caused by mutation in the CRAT gene (OMIM ).See review of Schneider and Bhatia (2012) on syndromes of neurodegeneration with brain iron accumulation, including Kufor-Rakeb disease (OMIM ) and aceruloplasminemia (OMIM ).

NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1; NBIA1 Is also known as hallervorden-spatz disease|pkan|pkan neuroaxonal dystrophy, juvenile-onset|pantothenate kinase-associated neurodegeneration

• Intellectual disability
• Seizures
• Global developmental delay
• Ataxia
• Failure to thrive

SOURCES: OMIM ORPHANET MENDELIAN