MedGen

GLB1-related disorders comprise two phenotypically distinct lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB). The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late-infantile and juvenile) to mild (chronic/adult). Type I (infantile) GM1 gangliosidosis begins before age 12 months. Prenatal manifestations may include nonimmune hydrops fetalis, intrauterine growth restriction, and placental vacuolization; congenital dermal melanocytosis (Mongolian spots) may be observed. Macular cherry-red spot is detected on eye exam. Progressive central nervous system dysfunction leads to spasticity and rapid regression; blindness, deafness, decerebrate rigidity, seizures, feeding difficulties, and oral secretions are observed. Life expectancy is two to three years. Type II can be subdivided into the late-infantile (onset age 1-3 years) and juvenile (onset age 3-10 years) phenotypes. Central nervous system dysfunction manifests as progressive cognitive, motor, and speech decline as measured by psychometric testing. There may be mild corneal clouding, hepatosplenomegaly, and/or cardiomyopathy; the typical course is characterized by progressive neurologic decline, progressive skeletal disease in some individuals (including kyphosis and avascular necrosis of the femoral heads), and progressive feeding difficulties leading to aspiration risk. Type III begins in late childhood to the third decade with generalized dystonia leading to unsteady gait and speech disturbance followed by extrapyramidal signs including akinetic-rigid parkinsonism. Cardiomyopathy develops in some and skeletal involvement occurs in most. Intellectual impairment is common late in the disease with prognosis directly related to the degree of neurologic impairment. MPS IVB is characterized by skeletal dysplasia with specific findings of axial and appendicular dysostosis multiplex, short stature (below 15th centile in adults), kyphoscoliosis, coxa/genu valga, joint laxity, platyspondyly, and odontoid hypoplasia. First signs and symptoms may be apparent at birth. Bony involvement is progressive, with more than 84% of adults requiring ambulation aids; life span does not appear to be limited. Corneal clouding is detected in some individuals and cardiac valvular disease may develop. [from GeneReviews]

D-bifunctional protein deficiency is a disorder of peroxisomal fatty acid beta-oxidation. See also peroxisomal acyl-CoA oxidase deficiency (264470), caused by mutation in the ACOX1 gene (609751) on chromosome 17q25. The clinical manifestations of these 2 deficiencies are similar to those of disorders of peroxisomal assembly, including X-linked adrenoleukodystrophy (ALD; 300100), Zellweger cerebrohepatorenal syndrome (see 214100) and neonatal adrenoleukodystrophy (NALD; see 601539) (Watkins et al., 1995). DBP deficiency has been classified into 3 subtypes depending upon the deficient enzyme activity. Type I is a deficiency of both 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase; type II is a deficiency of hydratase activity alone; and type III is a deficiency of dehydrogenase activity alone. Virtually all patients with types I, II, and III have a severe phenotype characterized by infantile-onset of hypotonia, seizures, and abnormal facial features, and most die before age 2 years. McMillan et al. (2012) proposed a type IV deficiency on the basis of less severe features; these patients have a phenotype reminiscent of Perrault syndrome (PRLTS1; 233400). Pierce et al. (2010) noted that Perrault syndrome and DBP deficiency overlap clinically and suggested that DBP deficiency may be underdiagnosed. [from OMIM]

Mitochondrial complex IV deficiency nuclear type 5 (MC4DN5) is an autosomal recessive severe metabolic multisystemic disorder with onset in infancy. Features include delayed psychomotor development, impaired intellectual development with speech delay, mild dysmorphic facial features, hypotonia, ataxia, and seizures. There is increased serum lactate and episodic hypoglycemia. Some patients may have cardiomyopathy, abnormal breathing, or liver abnormalities, reflecting systemic involvement. Brain imaging shows lesions in the brainstem and basal ganglia, consistent with a diagnosis of Leigh syndrome (see 256000). Affected individuals tend to have episodic metabolic and/or neurologic crises in early childhood, which often lead to early death (summary by Debray et al., 2011). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110. [from OMIM]

Mitochondrial complex IV deficiency nuclear type 6 (MC4DN6) is an autosomal recessive multisystem metabolic disorder with a highly variable phenotype. Some patients present in the neonatal period with encephalomyopathic features, whereas others present later in the first year of life with developmental regression. Manifestations include hypotonia, feeding difficulties, and global developmental delay. Many, but not all, patients develop hypertrophic cardiomyopathy, which may result in early death. Additional more variable features may include poor overall growth, microcephaly, seizures, neurodegeneration, spasticity, visual defects, retinopathy, and hepatic steatosis. Brain imaging in some patients shows features consistent with Leigh syndrome (see 256000). Laboratory studies show increased serum lactate and decreased levels and activity of mitochondrial respiratory complex IV (summary by Kennaway et al., 1990 and Oquendo et al., 2004). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110. [from OMIM]

Multiple mitochondrial dysfunctions syndrome is a severe autosomal recessive disorder of systemic energy metabolism, resulting in weakness, respiratory failure, lack of neurologic development, lactic acidosis, and early death (summary by Seyda et al., 2001). Genetic Heterogeneity of Multiple Mitochondrial Dysfunctions Syndrome See also MMDS2 (614299), caused by mutation in the BOLA3 gene (613183) on chromosome 2p13; MMDS3 (615330), caused by mutation in the IBA57 gene (615316) on chromosome 1q42; MMDS4 (616370), caused by mutation in the ISCA2 gene (615317) on chromosome 14q24; MMDS5 (617613), caused by mutation in the ISCA1 gene (611006) on chromosome 9q21; MMDS6 (617954), caused by mutation in the PMPCB gene (603131) on chromosome 7q22; and MMDS7 (620423), caused by mutation in the GCSH gene (238330) on chromosome 16q23. [from OMIM]

Dyskeratosis congenita and related telomere biology disorders (DC/TBD) are caused by impaired telomere maintenance resulting in short or very short telomeres. The phenotypic spectrum of telomere biology disorders is broad and includes individuals with classic dyskeratosis congenita (DC) as well as those with very short telomeres and an isolated physical finding. Classic DC is characterized by a triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia, although this may not be present in all individuals. People with DC/TBD are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome or acute myelogenous leukemia, solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Other findings can include eye abnormalities (epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trichiasis), taurodontism, liver disease, gastrointestinal telangiectasias, and avascular necrosis of the hips or shoulders. Although most persons with DC/TBD have normal psychomotor development and normal neurologic function, significant developmental delay is present in both forms; additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome and Coats plus syndrome). Onset and progression of manifestations of DC/TBD vary: at the mild end of the spectrum are those who have only minimal physical findings with normal bone marrow function, and at the severe end are those who have the diagnostic triad and early-onset BMF. [from GeneReviews]

Individuals with NGLY1-related congenital disorder of deglycosylation (NGLY1-CDDG) typically display a clinical tetrad of developmental delay / intellectual disability in the mild to profound range, hypo- or alacrima, elevated liver transaminases that may spontaneously resolve in childhood, and a complex hyperkinetic movement disorder that can include choreiform, athetoid, dystonic, myoclonic, action tremor, and dysmetric movements. About half of affected individuals will develop clinical seizures. Other findings may include obstructive and/or central sleep apnea, oral motor defects that affect feeding ability, auditory neuropathy, constipation, scoliosis, and peripheral neuropathy. [from GeneReviews]

Spastic paraplegia-81 (SPG81) is an autosomal recessive neurologic disorder with onset in infancy. Affected individuals have delayed motor development, progressive spasticity, and other neurologic impairment, including impaired intellectual development and speech delay. Some patients may have additional features, including bifid uvula, microcephaly, seizures, and variable ocular anomalies. One severely affected patient was reported to have cortical visual loss, sensorineural deafness, and achievement of almost no developmental milestones. Brain imaging shows white matter abnormalities, hypomyelination with progressive white matter loss, and sometimes cerebral atrophy. These significant additional abnormalities enable classification of this disorder as a complicated form of SPG (summary by Ahmed et al., 2017 and Horibata et al., 2018). For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800). [from OMIM]

Hypomyelinating leukodystrophy-15 is an autosomal recessive neurodegenerative disorder characterized by onset of motor and cognitive impairment in the first or second decade of life. Features include dystonia, ataxia, spasticity, and dysphagia. Most patients develop severe optic atrophy, and some have hearing loss. Brain imaging shows hypomyelinating leukodystrophy with thin corpus callosum. The severity of the disorder is variable (summary by Mendes et al., 2018) For a discussion of genetic heterogeneity of HLD, see 312080. [from OMIM]

NEDMEBA is an autosomal recessive neurodegenerative disorder characterized by global developmental delay, severe intellectual disability with poor or absent speech and autistic stereotypic behaviors, microcephaly, early-onset generalized seizures, and hypotonia (summary by Marin-Valencia et al., 2018). [from OMIM]

Hypomyelinating leukodystrophy-21 (HLD21) is an autosomal recessive neurodegenerative disorder characterized by global developmental delay apparent from infancy with loss of motor, speech, and cognitive milestones in the first decades of life. Affected individuals show cerebellar and pyramidal signs, including nystagmus, ataxia, dystonia, and spasticity, resulting in the loss of ambulation. Other more variable features include feeding difficulties, poor overall growth with microcephaly, optic atrophy, and seizures. Brain imaging shows diffuse hypomyelination of the white matter and atrophy of the cerebellum and corpus callosum. The disorder is progressive and may lead to premature death (summary by Dorboz et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see 312080. [from OMIM]

SOFM is characterized by marked short stature, oligodontia, mild facial dysmorphism, and motor delay. Endosteal hyperostosis has also been observed, and patients may exhibit some features of progeria (Terhal et al., 2020; Beauregard-Lacroix et al., 2020). [from OMIM]

AMED syndrome (AMEDS) is an autosomal recessive digenic multisystem disorder characterized by global developmental delay with impaired intellectual development, onset of bone marrow failure and myelodysplastic syndrome (MDS) in childhood, and poor overall growth with short stature (summary by Oka et al., 2020). For a discussion of genetic heterogeneity of bone marrow failure syndrome (BMFS), see BMFS1 (614675). [from OMIM]

Neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties (NEDSFF) is an autosomal recessive disorder characterized by distinct craniofacial features, multisystem dysfunction, profound neurodevelopmental delays, and neonatal death (Shankar et al., 2022). [from OMIM]