Delayed speech and language development, and Progressive neurologic deterioration

Medium match HYPERPHENYLALANINEMIA, BH4-DEFICIENT, A; HPABH4A

Tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (HPA) comprises a genetically heterogeneous group of progressive neurologic disorders caused by autosomal recessive mutations in the genes encoding enzymes involved in the synthesis or regeneration of BH4. BH4 is a cofactor for phenylalanine hydroxylase (PAH ), tyrosine hydroxylase (TH ) and tryptophan hydroxylase (TPH1 ), the latter 2 of which are involved in neurotransmitter synthesis. The BH4-deficient HPAs are characterized phenotypically by hyperphenylalaninemia, depletion of the neurotransmitters dopamine and serotonin, and progressive cognitive and motor deficits (Dudesek et al., 2001).HPABH4A, caused by mutations in the PTS gene, represents the most common cause of BH4-deficient hyperphenylalaninemia (Dudesek et al., 2001). Other forms of BH4-deficient HPA include HPABH4B (OMIM ), caused by mutation in the GCH1 gene (OMIM ), HPABH4C (OMIM ), caused by mutation in the QDPR gene (OMIM ), and HPABH4D (OMIM ), caused by mutation in the PCBD1 gene (OMIM ). Niederwieser et al. (1982) noted that about 1 to 3% of patients with hyperphenylalaninemia have one of these BH4-deficient forms. These disorders are clinically and genetically distinct from classic phenylketonuria (PKU ), caused by mutation in the PAH gene.Two additional disorders associated with BH4 deficiency and neurologic symptoms do not have overt hyperphenylalaninemia as a feature: dopa-responsive dystonia (OMIM ), caused by mutation in the SPR gene (OMIM ), and autosomal dominant dopa-responsive dystonia (DYT5 ), caused by mutation in the GCH1 gene. Patients with these disorders may develop hyperphenylalaninemia when stressed.

HYPERPHENYLALANINEMIA, BH4-DEFICIENT, A; HPABH4A Is also known as hyperphenylalaninemia, tetrahydrobiopterin-deficient, due to pts deficiency, 6-pyruvoyl-tetrahydropterin synthase deficiency, pts deficiency;hyperphenylalaninemia due to 6-pyruvoyltetrahydropterin synthase deficiency

• Autosomal recessive inheritance
• Intellectual disability
• Seizures
• Global developmental delay
• Generalized hypotonia

SOURCES: NCIT OMIM ORPHANET MONDO DOID MESH GARD UMLS

Medium match KOHLSCHUTTER-TONZ SYNDROME; KTZS

Kohlschutter-Tonz syndrome is an autosomal recessive disorder characterized by severe global developmental delay, early-onset intractable seizures, spasticity, and amelogenesis imperfecta affecting both primary and secondary teeth and causing yellow or brown discoloration of the teeth. Although the phenotype is consistent, there is variability. Intellectual disability is related to the severity of seizures, and the disorder can thus be considered an epileptic encephalopathy. Some infants show normal development until seizure onset, whereas others are delayed from birth. The most severely affected individuals have profound mental retardation, never acquire speech, and become bedridden early in life (summary by Schossig et al., 2012 and Mory et al., 2012).

KOHLSCHUTTER-TONZ SYNDROME; KTZS Is also known as epilepsy and yellow teeth, epilepsy, dementia, and amelogenesis imperfecta, kohlschutter syndrome;epilepsy-dementia-amelogenesis imperfecta syndrome; kohlschutter-tonz syndrome

• Autosomal recessive inheritance
• Intellectual disability
• Seizures
• Global developmental delay
• Short stature

SOURCES: MESH OMIM GARD SCTID MONDO ORPHANET UMLS

Medium match PITT-HOPKINS-LIKE SYNDROME 1; PTHSL1

Cortical dysplasia-focal epilepsy syndrome is a rare genetic epilepsy characterized by relatively large head circumference or macrocephaly, diminished or absent deep-tendon reflexes and mild gross motor delay in infancy, followed by intractable focal seizures with language regression, behavioral abnormalities (hyperactivity, attention deficit, aggressive/autoaggressive behavior, autistic features) and intellectual disability later in life.

PITT-HOPKINS-LIKE SYNDROME 1; PTHSL1 Is also known as cortical dysplasia-focal epilepsy syndrome;cdfes;cdfe syndrome; cdfes

• Intellectual disability
• Seizures
• Short stature
• Generalized hypotonia
• Pica

SOURCES: OMIM ORPHANET UMLS

Medium match LEUKODYSTROPHY, HYPOMYELINATING, 3; HLD3

Autosomal recessive hypomyelinating leukodystrophy-3 (HLD3) is a severe neurologic disorder characterized by early infantile onset of global developmental delay, lack of development, lack of speech acquisition, and peripheral spasticity associated with decreased myelination in the central nervous system (summary by Feinstein et al., 2010).The disorder is phenotypically similar to X-linked Pelizaeus-Merzbacher disease (PMD ), which is caused by mutation in the PLP1 gene (OMIM ). For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see {312080}.

LEUKODYSTROPHY, HYPOMYELINATING, 3; HLD3 Is also known as ;

• Autosomal recessive inheritance
• Intellectual disability
• Seizures
• Global developmental delay
• Generalized hypotonia

SOURCES: GARD DOID ORPHANET MONDO OMIM UMLS MESH

Medium match LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER; VWM

Vanishing white matter leukodystrophy is an autosomal recessive neurologic disorder characterized by variable neurologic features, including progressive cerebellar ataxia, spasticity, and cognitive impairment associated with white matter lesions on brain imaging. The age at onset can range from early infancy to adulthood. Rapid neurologic deterioration can occur following minor head trauma. Female mutation carriers may develop ovarian failure, manifest as primary amenorrhea or as secondary amenorrhea lasting more than 6 months, associated with elevated gonadotropin levels at age less than 40 years (summary by Van der Knaap et al., 1998 and Schiffmann et al., 1997).

LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER; VWM Is also known as childhood ataxia with central nervous system hypomyelinization;cach, vanishing white matter leukodystrophy, cree leukoencephalopathy;cle

• Autosomal recessive inheritance
• Seizures
• Generalized hypotonia
• Pica
• Ataxia

SOURCES: ORPHANET OMIM

Medium match HSD10 MITOCHONDRIAL DISEASE; HSD10MD

HSD10 mitochondrial disease most commonly presents as an X-linked neurodegenerative disorder with highly variable severity and age at onset ranging from the neonatal period to early childhood. The features are usually multisystemic, consistent with mitochondrial dysfunction. Some affected males have a severe infantile form associated with cardiomyopathy that may result in death in early childhood, whereas other rare patients may have juvenile onset or even atypical presentations with normal neurologic development. More severely affected males show developmental regression in infancy or early childhood, often associated with early-onset intractable seizures, progressive choreoathetosis and spastic tetraplegia, optic atrophy or retinal degeneration resulting in visual loss, and mental retardation. Heterozygous females may show non-progressive developmental delay and intellectual disability, but may also be clinically normal. Although the diagnosis can be aided by the observation of increased urinary levels of metabolites of isoleucine breakdown (2-methyl-3 hydroxybutyrate and tiglylglycine), there is not a correlation between these laboratory features and the phenotype. In addition, patients do not develop severe metabolic crises in the neonatal period as observed in other organic acidurias, but may show persistent lactic acidosis, most likely reflecting mitochondrial dysfunction (summary by Rauschenberger et al., 2010; review by Zschocke, 2012).In a review of the disorder, Zschocke (2012) noted that although this disorder was originally thought to be an inborn error of branched-chain fatty acid and isoleucine metabolism resulting from decreased HSD17B10 dehydrogenase activity (HSD17B10 'deficiency'), subsequent studies have shown that the HSD17B10 gene product has additional functions and also acts as a component of the mitochondrial RNase P holoenzyme, which is involved in mitochondrial tRNA processing and maturation and ultimately mitochondrial protein synthesis. The multisystemic features of HSD10MD most likely result from the adverse effect of HSD17B10 mutations on mitochondrial function, rather than from the effects on the dehydrogenase activity (see PATHOGENESIS below).

HSD10 MITOCHONDRIAL DISEASE; HSD10MD Is also known as hsd17b10 deficiency, 17-beta-hydroxysteroid dehydrogenase x deficiency, 3-hydroxyacyl-coa dehydrogenase ii deficiency, 2-methyl-3-hydroxybutyryl-coa dehydrogenase deficiency, mhbd deficiency, mental retardation, x-linked, syndromic 10;mrxs10, chorioathetosis with mental retardation and abnormal behavior;camr, mental retardation with chorioathetosis and abnormal behavior

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

SOURCES: SCTID ORPHANET UMLS OMIM

Medium match ENCEPHALOPATHY, PROGRESSIVE, WITH OR WITHOUT LIPODYSTROPHY; PELD

Progressive encephalopathy with or without lipodystrophy is a severe neurodegenerative disorder characterized by developmental regression of motor and cognitive skills in the first years of life, often leading to death in the first decade. Patients may show a mild or typical lipodystrophic appearance (summary by Guillen-Navarro et al., 2013).

ENCEPHALOPATHY, PROGRESSIVE, WITH OR WITHOUT LIPODYSTROPHY; PELD Is also known as ;severe neurodegenerative syndrome due to bscl2 deficiency

• Autosomal recessive inheritance
• Seizures
• Global developmental delay
• Ataxia
• Motor delay

SOURCES: ORPHANET OMIM MONDO UMLS

Medium match AICARDI-GOUTIERES SYNDROME 7; AGS7

Aicardi-Goutieres syndrome-7 is an autosomal dominant inflammatory disorder characterized by severe neurologic impairment. Most patients present in infancy with delayed psychomotor development, axial hypotonia, spasticity, and brain imaging changes, including basal ganglia calcification, cerebral atrophy, and deep white matter abnormalities. Laboratory evaluation shows increased alpha-interferon (IFNA1 ) activity with upregulation of interferon signaling and interferon-stimulated gene expression. Some patients may have normal early development followed by episodic neurologic regression (summary by Rice et al., 2014).For a phenotypic description and a discussion of genetic heterogeneity of Aicardi-Goutieres syndrome, see AGS1 (OMIM ).

• Autosomal dominant inheritance
• Intellectual disability
• Seizures
• Global developmental delay
• Generalized hypotonia

SOURCES: UMLS MONDO OMIM

Medium match HUNTINGTON DISEASE; HD

Huntington disease (HD) is an autosomal dominant progressive neurodegenerative disorder with a distinct phenotype characterized by chorea, dystonia, incoordination, cognitive decline, and behavioral difficulties. There is progressive, selective neural cell loss and atrophy in the caudate and putamen. Walker (2007) provided a detailed review of Huntington disease, including clinical features, population genetics, molecular biology, and animal models.

HUNTINGTON DISEASE; HD Is also known as huntington chorea;huntington chorea

• Autosomal dominant inheritance
• Seizures
• Pica
• Ataxia
• Cognitive impairment

SOURCES: ORPHANET OMIM UMLS ICD10 SCTID

Medium match MUCOPOLYSACCHARIDOSIS, TYPE IIIA; MPS3A

The Sanfilippo syndrome, or mucopolysaccharidosis III, is an autosomal recessive lysosomal storage disease due to impaired degradation of heparan sulfate (Esposito et al., 2000). The disorder is characterized by severe central nervous system degeneration, but only mild somatic disease. Onset of clinical features usually occurs between 2 and 6 years; severe neurologic degeneration occurs in most patients between 6 and 10 years of age, and death occurs typically during the second or third decade of life. Type A has been reported (van de Kamp et al., 1981) to be the most severe, with earlier onset and rapid progression of symptoms and shorter survival. Genetic Heterogeneity of Mucopolysaccharidosis Type IIIMPS III includes 4 types, each due to the deficiency of a different enzyme: heparan N-sulfatase (type A); alpha-N-acetylglucosaminidase (type B; {252920}); acetyl CoA:alpha-glucosaminide acetyltransferase (type C; {252930}); and N-acetylglucosamine 6-sulfatase (type D; {252940}).

MUCOPOLYSACCHARIDOSIS, TYPE IIIA; MPS3A Is also known as mps iiia, sanfilippo syndrome a, heparan sulfate sulfatase deficiency, sulfamidase deficiency

• Autosomal recessive inheritance
• Intellectual disability
• Seizures
• Global developmental delay
• Hearing impairment

SOURCES: OMIM NCIT