Delayed speech and language development, and Urinary incontinence

Medium match EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION; FESD

Focal epilepsy with speech disorder is a childhood-onset seizure disorder with a highly variable phenotype. Seizures typically occur in the temporal lobe, or rolandic brain region, which affects speech and language, and electroencephalogram (EEG) characteristically shows centrotemporal spike-wave discharges. EEG abnormalities often occur during sleep and may manifest as continuous spike-wave discharges during slow-wave sleep (CSWS or CSWSS). FESD represents an electroclinical spectrum that ranges from severe early-onset seizures associated with delayed psychomotor development, persistent speech difficulties, and mental retardation to a more benign entity characterized by childhood onset of mild or asymptomatic seizures associated with transient speech difficulties followed by remission of seizures in adolescence and normal psychomotor development. There is incomplete penetrance and intrafamilial variability, even among family members who carry the same GRIN2A mutation (summary by Lesca et al., 2013; Lemke et al., 2013; Carvill et al., 2013).The disorder represented here encompasses several clinical entities, including Landau-Kleffner syndrome (LKS), epileptic encephalopathy with continuous spike and wave during slow-wave sleep (ECSWS; CSWSS), autosomal dominant rolandic epilepsy, mental retardation, and speech dyspraxia (ADRESD; RESDAD), and benign epilepsy with centrotemporal spikes (BECTS; see {117100}). LKS is classically described as a childhood-onset variant of epileptic aphasia. It is associated with EEG abnormalities occurring in the temporal lobe of the language-dominant hemisphere, even in the absence of overt clinical seizures. LKS is sometimes referred to as an 'acquired aphasia' because most affected children show normal psychomotor development until the onset of seizures, usually between 3 and 7 years, although some may have prior delayed development. A hallmark of the disorder is severe impairment in auditory language comprehension and speech. Some patients may also have persistent intellectual disability or behavioral abnormalities reminiscent of autism or attention deficit-hyperactivity disorder. EEG abnormalities typically include centrotemporal spikes suggestive of rolandic epilepsy or continuous spike and waves during slow-wave sleep. The presence of CSWS is associated with more widespread behavioral and cognitive regression than LKS, although the 2 disorders may be considered part of a spectrum. There is controversy about the precise definition of LKS and its relationship to CSWS that stems mainly from the phenotypic heterogeneity of the disorder (summary by Stefanatos, 2011).

EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION; FESD Is also known as aphasia, acquired, with epilepsy

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

SOURCES: OMIM

Medium match PARKINSON DISEASE 1, AUTOSOMAL DOMINANT; PARK1

Parkinson disease is the second most common neurogenic disorder after Alzheimer disease (AD ), affecting approximately 1% of the population over age 50. Clinical manifestations include resting tremor, muscular rigidity, bradykinesia, and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia (Polymeropoulos et al., 1996).For a general phenotypic description and a discussion of genetic heterogeneity of Parkinson disease, see {168600}.

PARKINSON DISEASE 1, AUTOSOMAL DOMINANT; PARK1 Is also known as parkinson disease 1, autosomal dominant lewy body

• Autosomal dominant inheritance
• Pica
• Spasticity
• Delayed speech and language development
• Hyperreflexia

SOURCES: DOID UMLS OMIM MESH MONDO

Medium match GM1-GANGLIOSIDOSIS, TYPE III

GM1-gangliosidosis type III is an autosomal recessive lysosomal storage disorder characterized by neurodegeneration and mild skeletal changes. Age at onset ranges from 3 to 30 years. The disorder is less severe than GM1-gangliosidosis types I and II (OMIM ). Type III shows extreme clinical variability, with some patients having only focal neurologic signs, such as dystonia, and others having more severe involvement with extrapyramidal signs and mental retardation. GLB1 enzymatic activity usually ranges from approximately 4 to 10% of control values (Suzuki et al., 2001).

GM1-GANGLIOSIDOSIS, TYPE III Is also known as gangliosidosis, generalized gm1, adult type, gangliosidosis, generalized gm1, chronic type, gangliosidosis, generalized gm1, type iii, gangliosidosis, generalized gm1, type 3;adult-onset gm1 gangliosidosis

• Autosomal recessive inheritance
• Intellectual disability
• Seizures
• Short stature
• Scoliosis

SOURCES: OMIM GARD UMLS SCTID ORPHANET MONDO

Medium match 3-METHYLGLUTACONIC ACIDURIA, TYPE I; MGCA1

Type I MGCA is a rare autosomal recessive disorder of leucine catabolism. The metabolic landmark is urinary excretion of 3-methylglutaconic acid (3-MGA) and its derivatives 3-methylglutaric acid (3-MG) and 3-hydroxyisovaleric acid (3-HIVA). Two main presentations have been described: 1 with onset in childhood associated with the nonspecific finding of psychomotor retardation, and the other with onset in adulthood of a progressive neurodegenerative disorder characterized by ataxia, spasticity, and sometimes dementia; these patients develop white matter lesions in the brain. However, some asymptomatic pediatric patients have been identified by newborn screening and show no developmental abnormalities when reexamined later in childhood (summary by Wortmann et al., 2010). Genetic Heterogeneity and Classification of Methylglutaconic AciduriaMethylglutaconic aciduria is a clinically and genetically heterogeneous disorder. Type II MGCA (MGCA2), also known as Barth syndrome (BTHS ), is caused by mutation in the tafazzin gene (TAZ ) on chromosome Xq28. It is characterized by mitochondrial cardiomyopathy, short stature, skeletal myopathy, and recurrent infections; cognitive development is normal. Type III MGCA (MGCA3 ), caused by mutation in the OPA3 gene (OMIM ) on chromosome 19q13, involves optic atrophy, movement disorder, and spastic paraplegia. In types II and III, the elevations of 3-methylglutaconate and 3-methylglutarate in urine are modest. Type IV MGCA (MGCA4 ) represents an unclassified group of patients who have severe psychomotor retardation and cerebellar dysgenesis. Type V MGCA (MGCA5 ), caused by mutation in the DNAJC19 gene (OMIM ) on chromosome 3q26, is characterized by early-onset dilated cardiomyopathy with conduction defects, nonprogressive cerebellar ataxia, testicular dysgenesis, and growth failure in addition to 3-methylglutaconic aciduria (Chitayat et al., 1992; Davey et al., 2006). Type VI MGCA (MGCA6 ), caused by mutation in the SERAC1 gene (OMIM ) on chromosome 6q25, includes deafness, encephalopathy, and a Leigh-like syndrome. Type VII MGCA (MGCA7 ), caused by mutation in the CLPB gene (OMIM ) on chromosome 11q13, includes cataracts, neurologic involvement, and neutropenia. Type VIII MCGA (MGCA8 ) is caused by mutation in the HTRA2 gene (OMIM ) on chromosome 2p13. Type IX MCGA (MGCA9 ) is caused by mutation in the TIMM50 gene (OMIM ) on chromosome 19q13.Eriguchi et al. (2006) noted that type I MGCA is very rare, with only 13 patients reported in the literature as of 2003.Wortmann et al. (2013) proposed a pathomechanism-based classification for 'inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature.'

3-METHYLGLUTACONIC ACIDURIA, TYPE I; MGCA1 Is also known as mga, type i;mga1, 3-methylglutaconyl-coa hydratase deficiency, 3-mg-coa-hydratase deficiency;3-methylglutaconyl-coa hydratase deficiency; 3mg-coa hydratase deficiency; mga1

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

SOURCES: SCTID ORPHANET MONDO MESH OMIM NCIT UMLS GARD DOID

Medium match NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4; NBIA4

Neurodegeneration with brain iron accumulation-4 (NBIA4) is an autosomal recessive neurodegenerative disorder characterized by progressive spastic paraplegia, parkinsonism unresponsive to L-DOPA treatment, and psychiatric or behavioral symptoms. Other neurologic features, including optic atrophy, eye movement abnormalities, dystonia, dysphagia, dysarthria, and motor axonal neuropathy, may occur. Brain MRI shows T2-weighted hypointensities in the globus pallidus and substantia nigra. Onset is usually in the first 2 decades, but later onset has been reported (summary by Dogu et al., 2013). There is phenotypic variation: some patients may not have extrapyramidal signs and may have muscle weakness and atrophy as well as cognitive impairment or developmental delay (Deschauer et al., 2012)For a general phenotypic description and a discussion of genetic heterogeneity of NBIA, see NBIA1 (OMIM ).

NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4; NBIA4 Is also known as mitochondrial protein-associated neurodegeneration;mpan;mpan; nbia due to c19orf12 mutation; nbia4; neurodegeneration with brain iron accumulation due to c19orf12 mutation; neurodegeneration with brain iron accumulation type 4

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

SOURCES: OMIM DOID SCTID GARD UMLS ORPHANET MONDO

Medium match MENTAL RETARDATION, X-LINKED, SYNDROMIC, CHRISTIANSON TYPE; MRXSCH

Christianson syndrome is an X-linked neurodevelopmental and progressive mental retardation syndrome characterized by microcephaly, impaired ocular movements, severe global developmental delay, developmental regression, hypotonia, abnormal movements, and early-onset seizures of variable types. Female carriers may be mildly affected (summary by Schroer et al., 2010 and Pescosolido et al., 2014).

MENTAL RETARDATION, X-LINKED, SYNDROMIC, CHRISTIANSON TYPE; MRXSCH Is also known as angelman-like syndrome, x-linked, mental retardation, microcephaly, epilepsy, and ataxia syndrome;x-linked angelman-like syndrome; x-linked intellectual disability, south african type; x-linked intellectual disability-craniofacial dysmorphism-epilepsy-ophthalmoplegia-cerebellar atrophy syndrome

• Intellectual disability
• Seizures
• Global developmental delay
• Generalized hypotonia
• Microcephaly

SOURCES: ORPHANET MONDO GARD OMIM DOID UMLS MESH SCTID

Medium match ALLAN-HERNDON-DUDLEY SYNDROME; AHDS

Allan-Herndon-Dudley syndrome (AHDS) is an X-linked intellectual disability syndrome with neuromuscular involvement characterized by infantile hypotonia, muscular hypoplasia, spastic paraparesis with dystonic/athetoic movements, and severe cognitive deficiency.

ALLAN-HERNDON-DUDLEY SYNDROME; AHDS Is also known as allan-herndon syndrome, monocarboxylate transporter 8 deficiency, triiodothyronine resistance, t3 resistance, mental retardation, x-linked, with hypotonia, mental retardation and muscular atrophy;ahds; mct8 deficiency; monocarboxylate transporter 8 deficiency; x-linked intellectual disability-hypotonia syndrome

• Intellectual disability
• Global developmental delay
• Generalized hypotonia
• Pica
• Microcephaly

SOURCES: UMLS SCTID ORPHANET MONDO GARD NCIT OMIM DOID MESH

Medium match SPASTIC PARAPLEGIA 48, AUTOSOMAL RECESSIVE; SPG48

Autosomal recessive spastic paraplegia type 48 is a form of hereditary spastic paraplegia usually characterized by a pure phenotype of a slowly progressive spastic paraplegia associated with urinary incontinence with an onset in mid- to late-adulthood. A complex phenotype, with the additional findings of cognitive impairment, sensorimotor polyneuropathy, ataxia and parkinsonism, as well as thin corpus callosum and white matter lesions (seen on magnetic resonance imaging), has also been reported.

SPASTIC PARAPLEGIA 48, AUTOSOMAL RECESSIVE; SPG48 Is also known as ;spg48

• Autosomal recessive inheritance
• Intellectual disability
• Global developmental delay
• Ataxia
• Cognitive impairment

SOURCES: DOID OMIM MONDO ORPHANET UMLS

Medium match METACHROMATIC LEUKODYSTROPHY DUE TO SAPOSIN B DEFICIENCY

METACHROMATIC LEUKODYSTROPHY DUE TO SAPOSIN B DEFICIENCY Is also known as metachromatic leukodystrophy due to cerebroside sulfatase activator deficiency, saposin b deficiency

• Autosomal recessive inheritance
• Seizures
• Global developmental delay
• Generalized hypotonia
• Muscular hypotonia

SOURCES: MONDO SCTID GARD OMIM MESH

Medium match CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2Z; CMT2Z

Charcot-Marie-Tooth disease type 2Z (CMT2Z) is an autosomal dominant peripheral neuropathy characterized by onset, usually in the first decade, of distal lower limb muscle weakness and sensory impairment. The disorder is progressive, and affected individuals tend to develop upper limb and proximal muscle involvement in an asymmetric pattern, resulting in severe disability late in adulthood (summary by Sevilla et al., 2016).For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (OMIM ).

CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2Z; CMT2Z Is also known as charcot-marie-tooth disease, axonal, autosomal dominant, type 2z, charcot-marie-tooth neuropathy, type 2z;autosomal dominant charcot-marie-tooth disease type 2 due to morc2 mutation; cmt2z

• Autosomal dominant inheritance
• Global developmental delay
• Generalized hypotonia
• Pica
• Hearing impairment

SOURCES: UMLS OMIM DOID ORPHANET MONDO