Cognitive impairment, and Premature birth

CONDBA is a severe progressive neurodegenerative disorder characterized by loss of motor and cognitive skills between ages 2 and 7 years. Affected individuals may have normal development or mild developmental delay, but all eventually lose all motor skills, resulting in inability to walk, absence of language, and profound intellectual disability. Brain imaging shows progressive cerebral and cerebellar atrophy (summary by Edvardson et al., 2017).

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

SOURCES: ORPHANET OMIM MENDELIAN

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}.

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

SOURCES: ORPHANET MESH OMIM MENDELIAN

Rubinstein-Taybi syndrome (RSTS) is a multiple congenital anomaly syndrome characterized by mental retardation, postnatal growth deficiency, microcephaly, broad thumbs and halluces, and dysmorphic facial features. The classic facial appearance is striking, with highly arched eyebrows, long eyelashes, downslanting palpebral fissures, broad nasal bridge, beaked nose with the nasal septum, highly arched palate, mild micrognathia, and characteristic grimacing or abnormal smile (Rubinstein and Taybi, 1963; review by Hennekam, 2006).About 50 to 70% of patients have RSTS1 due to mutation in the CREBBP gene (OMIM ). RSTS2 is much less common, and about 3% of patients have mutations in the EP300 gene. RSTS2 appears to be associated with a milder phenotype than RSTS1. Patients with RSTS2 have less severe facial dysmorphism and better cognitive function, but may have more severe microcephaly and malformation of facial bone structures compared to those with RSTS1 (Bartsch et al., 2010).For a discussion of genetic heterogeneity of Rubinstein-Taybi syndrome, see RSTS1 (OMIM ).

• Intellectual disability
• Global developmental delay
• Short stature
• Microcephaly
• Scoliosis

SOURCES: ORPHANET OMIM MENDELIAN

Pelizaeus-Merzbacher disease is an X-linked recessive hypomyelinative leukodystrophy (HLD1) in which myelin is not formed properly in the central nervous system. PMD is characterized clinically by nystagmus, spastic quadriplegia, ataxia, and developmental delay (Inoue, 2005). Genetic Heterogeneity of Hypomyelinating LeukodystrophyOther forms of hypomyelinating leukodystrophy include HLD2 (OMIM ), caused by mutation in the GJC2/GJA12 gene (OMIM ) on chromosome 1q41; HLD3 (OMIM ), caused by mutation in the AIMP1 gene (OMIM ) on chromosome 4q24; HLD4 (OMIM ), caused by mutation in the HSPD1 gene (OMIM ) on chromosome 2q33.1; and HLD5 (OMIM ), caused by mutation in the FAM126A gene (OMIM ) on chromosome 7p15; HLD6 (OMIM ), caused by mutation in the TUBB4A gene (OMIM ) on chromosome 19p13; HLD7 (OMIM ), caused by mutation in the POLR3A gene (OMIM ) on chromosome 10q22; HLD8 (OMIM ), caused by mutation in the POLR3B gene (OMIM ) on chromosome 12q23; HLD9 (OMIM ), caused by mutation in the RARS gene (OMIM ) on chromosome 5; HLD10 (OMIM ), caused by mutation in the PYCR2 gene (OMIM ) on chromosome 1q42; HLD11 (OMIM ), caused by mutation in the POLR1C gene (OMIM ) on chromosome 6p21; HLD12 (OMIM ), caused by mutation in the VPS11 gene (OMIM ) on chromosome 11q23; HLD13 (OMIM ) caused by mutation in the HIKESHI gene (OMIM ) on chromosome 11q14; HLD14 (OMIM ), caused by mutation in the UFM1 gene (OMIM ) on chromosome 13q13; HLD15 (OMIM ), caused by mutation in the EPRS gene (OMIM ) on chromosome 1q41; HLD16 (OMIM ), caused by mutation in the TMEM106B gene (OMIM ) on chromosome 7p21; and HLD17 (OMIM ), caused by mutation in the AIMP2 gene (OMIM ) on chromosome 7p22.

PELIZAEUS-MERZBACHER DISEASE; PMD Is also known as leukodystrophy, hypomyelinating, 1|hld1

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

SOURCES: ORPHANET OMIM MENDELIAN

Myotonic dystrophy is an autosomal dominant disorder characterized mainly by myotonia, muscular dystrophy, cataracts, hypogonadism, frontal balding, and ECG changes. The genetic defect in DM1 results from an amplified trinucleotide repeat in the 3-prime untranslated region of a protein kinase gene. Disease severity varies with the number of repeats: normal individuals have 5 to 37 repeats, mildly affected persons have 50 to 150 repeats, patients with classic DM have 100 to 1,000 repeats, and those with congenital onset can have more than 2,000 repeats. The disorder shows genetic anticipation, with expansion of the repeat number dependent on the sex of the transmitting parent. Alleles of 40 to 80 repeats are usually expanded when transmitted by males, whereas only alleles longer than 80 repeats tend to expand in maternal transmissions. Repeat contraction events occur 4.2 to 6.4% of the time (Musova et al., 2009). Genetic Heterogeneity of Myotonic DystrophySee also myotonic dystrophy-2 (DM2 ), which is caused by mutation in the ZNF9 gene (OMIM ) on chromosome 3q21.

MYOTONIC DYSTROPHY 1; DM1 Is also known as dystrophia myotonica 1|dystrophia myotonica|steinert disease|dm

• Intellectual disability
• Seizures
• Generalized hypotonia
• Muscle weakness
• Muscular hypotonia

SOURCES: OMIM MENDELIAN

Syndromic diarrhea (SD), or tricho-hepato-enteric syndrome (THE), is a severe congenital enteropathy manifesting as intractable diarrhea in the first month of life with failure to thrive and associated with facial dysmorphism, hair abnormalities, and, in some cases, immune disorders and intrauterine growth restriction.

SYNDROMIC DIARRHEA Is also known as trichohepatoenteric syndrome|tricho-hepato-enteric syndrome|diarrhea, fatal infantile, with trichorrhexis nodosa|sd/the|the syndrome|phenotypic diarrhea|diarrhea, syndromic|syndromic diarrhea/tricho-hepato-enteric syndrome

• Intellectual disability
• Global developmental delay
• Short stature
• Growth delay
• Hypertelorism

SOURCES: OMIM ORPHANET MENDELIAN

Fetal Gaucher disease is the perinatal lethal form of Gaucher disease (GD; see this term).

FETAL GAUCHER DISEASE Is also known as perinatal lethal gaucher disease|gaucher disease, collodion type

• Seizures
• Generalized hypotonia
• Microcephaly
• Hypertelorism
• Micrognathia

SOURCES: ORPHANET MESH OMIM MENDELIAN

Adams-Oliver Syndrome (AOS) is a rare disorder characterized by the combination of congenital limb abnormalities and scalp defects, often accompanied by skull ossification defects.

ADAMS-OLIVER SYNDROME Is also known as aplasia cutis congenita with terminal transverse limb defects|congenital scalp defects with distal limb reduction anomalies|congenital scalp defects with distal limb anomalies|aos|absence defect of limbs, scalp, and skull|limb, scalp and skull defects

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

SOURCES: ORPHANET OMIM MENDELIAN

Schimke immuno-osseous dysplasia (SIOD) is a multisystem disorder characterized by spondyloepiphyseal dysplasia and disproportionate short stature, facial dysmorphism, T-cell immunodeficiency, and glomerulonephritis with nephrotic syndrome.

SCHIMKE IMMUNO-OSSEOUS DYSPLASIA Is also known as immunoosseous dysplasia, schimke type|schimke syndrome|spondyloepiphyseal dysplasia-nephrotic syndrome

• Intellectual disability
• Seizures
• Short stature
• Scoliosis
• Growth delay

SOURCES: OMIM ORPHANET MESH MENDELIAN

Isolated complex I deficiency is a rare inborn error of metabolism due to mutations in nuclear or mitochondrial genes encoding subunits or assembly factors of the human mitochondrial complex I (NADH: ubiquinone oxidoreductase) and is characterized by a wide range of manifestations including marked and often fatal lactic acidosis, cardiomyopathy, leukoencephalopathy, pure myopathy and hepatopathy with tubulopathy. Among the numerous clinical phenotypes observed are Leigh syndrome, Leber hereditary optic neuropathy and MELAS syndrome (see these terms).

ISOLATED COMPLEX I DEFICIENCY Is also known as isolated nadh-ubiquinone reductase deficiency|nadh:q(1) oxidoreductase deficiency|isolated nadh-coq reductase deficiency|isolated mitochondrial respiratory chain complex i deficiency|isolated nadh-coenzyme q reductase deficiency|nadh-coenzyme q reductase

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

SOURCES: ORPHANET MESH OMIM MENDELIAN