Niemann-Pick disease, type A- MedGen UID:
- 78650
- •Concept ID:
- C0268242
- •
- Disease or Syndrome
The phenotype of acid sphingomyelinase deficiency (ASMD) occurs along a continuum. Individuals with the severe early-onset form, infantile neurovisceral ASMD, were historically diagnosed with Niemann-Pick disease type A (NPD-A). The later-onset, chronic visceral form of ASMD is also referred to as Niemann-Pick disease type B (NPD-B). A phenotype with intermediate severity is also known as chronic neurovisceral ASMD (NPD-A/B). The most common presenting symptom in NPD-A is hepatosplenomegaly, usually detectable by age three months; over time the liver and spleen become massive in size. Psychomotor development progresses no further than the 12-month level, after which neurologic deterioration is relentless. Failure to thrive typically becomes evident by the second year of life. A classic cherry-red spot of the macula of the retina, which may not be present in the first few months, is eventually present in all affected children. Interstitial lung disease caused by storage of sphingomyelin in pulmonary macrophages results in frequent respiratory infections and often respiratory failure. Most children succumb before the third year of life. NPD-B generally presents later than NPD-A, and the manifestations are less severe. NPD-B is characterized by progressive hepatosplenomegaly, gradual deterioration in liver and pulmonary function, osteopenia, and atherogenic lipid profile. No central nervous system (CNS) manifestations occur. Individuals with NPD-A/B have symptoms that are intermediate between NPD-A and NPD-B. The presentation in individuals with NPD-A/B varies greatly, although all are characterized by the presence of some CNS manifestations. Survival to adulthood can occur in individuals with NPD-B and NPD-A/B.
Pyogenic arthritis-pyoderma gangrenosum-acne syndrome- MedGen UID:
- 346801
- •Concept ID:
- C1858361
- •
- Disease or Syndrome
Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) is a rare autosomal dominant autoinflammatory disease that typically presents with recurrent sterile, erosive arthritis in childhood, occurring spontaneously or after minor trauma, occasionally resulting in significant joint destruction. By puberty, joint symptoms tend to subside and cutaneous symptoms predominate, including pathergy, frequently with abscesses at the sites of injections, severe cystic acne, and recurrent nonhealing sterile ulcers, often diagnosed as pyoderma gangrenosum (summary by Demidowich et al., 2012).
Dominant beta-thalassemia- MedGen UID:
- 347036
- •Concept ID:
- C1858990
- •
- Disease or Syndrome
Dominantly inherited inclusion body beta-thalassemia is characterized by the presence of inclusion bodies in red blood cell precursors, moderately severe anemia, jaundice, and splenomegaly (summary by Ropero et al., 2005).
Majeed syndrome- MedGen UID:
- 351273
- •Concept ID:
- C1864997
- •
- Disease or Syndrome
Majeed syndrome (MJDS) is an autosomal recessive pediatric multisystem autoinflammatory disorder characterized by chronic recurrent multifocal osteomyelitis (CRMO) and congenital dyserythropoietic anemia; some patients may also develop neutrophilic dermatosis. Additional features may include fever, failure to thrive, and neutropenia. Laboratory studies show elevated inflammatory markers consistent with activation of the proinflammatory IL1 (147760) pathway (summary by Ferguson and El-Shanti, 2021).
Genetic Heterogeneity of Chronic Recurrent Multifocal Osteomyelitis
See also CRMO2 (612852), caused by mutation in the IL1RN gene (147679) on chromosome 2q14; and CRMO3 (259680), caused by mutation in the IL1R1 gene (147810) on chromosome 2q12.
Craniofacial dysplasia - osteopenia syndrome- MedGen UID:
- 370148
- •Concept ID:
- C1970027
- •
- Disease or Syndrome
A rare genetic developmental defect during embryogenesis disorder with characteristics of craniofacial dysmorphism (including brachycephaly, prominent forehead, sparse lateral eyebrows, severe hypertelorism, upslanting palpebral fissures, epicanthal folds, protruding ears, broad nasal bridge, pointed nasal tip, flat philtrum, anteverted nostrils, large mouth, thin upper vermilion border, highly arched palate and mild micrognathia) associated with osteopenia leading to repeated long bone fractures, severe myopia, mild to moderate sensorineural or mixed hearing loss, enamel hypoplasia, sloping shoulders and mild intellectual disability. There is evidence the disease can be caused by homozygous mutation in the IRX5 gene on chromosome 16q11.2.
Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria- MedGen UID:
- 413170
- •Concept ID:
- C2749864
- •
- Disease or Syndrome
SUCLA2-related mitochondrial DNA (mtDNA) depletion syndrome, encephalomyopathic form with methylmalonic aciduria is characterized by onset of the following features in infancy or childhood (median age of onset 2 months; range of onset birth to 6 years): psychomotor retardation, hypotonia, dystonia, muscular atrophy, sensorineural hearing impairment, postnatal growth retardation, and feeding difficulties. Other less frequent features include distinctive facial features, contractures, kyphoscoliosis, gastroesophageal reflux, ptosis, choreoathetosis, ophthalmoplegia, and epilepsy (infantile spasms or generalized convulsions). The median survival is 20 years; approximately 30% of affected individuals succumb during childhood. Affected individuals may have hyperintensities in the basal ganglia, cerebral atrophy, and leukoencephalopathy on head MRI. Elevation of methylmalonic acid (MMA) in the urine and plasma is found in a vast majority of affected individuals, although at levels that are far below those typically seen in individuals with classic methylmalonic aciduria.
SRD5A3-congenital disorder of glycosylation- MedGen UID:
- 1392124
- •Concept ID:
- C4317224
- •
- Disease or Syndrome
SRD5A3-congenital disorder of glycosylation (SRD5A3-CDG, formerly known as congenital disorder of glycosylation type Iq) is an inherited condition that causes neurological and vision problems and other signs and symptoms. The pattern and severity of this condition's features vary widely among affected individuals.\n\nIndividuals with SRD5A3-CDG typically develop signs and symptoms of the condition during infancy or early childhood. Most individuals with SRD5A3-CDG have intellectual disability, vision problems, unusual facial features,low muscle tone (hypotonia), and problems with coordination and balance (ataxia). \n\nVision problems in SRD5A3-CDG often include involuntary side-side movements of the eyes (nystagmus), a gap or hole in one of the structures of the eye (coloboma), underdevelopment of the nerves that carry signals between the eyes and the brain(optic nerve hypoplasia), or vision loss early in life (early-onset severe retinal dystrophy). Over time, affected individuals may develop clouding of the lenses of the eyes (cataracts) or increased pressure in the eyes (glaucoma).\n\nOther features of SRD5A3-CDG can include skin rash, unusually small red blood cells (microcytic anemia),and liver problems.
Myopathy, lactic acidosis, and sideroblastic anemia 1- MedGen UID:
- 1634824
- •Concept ID:
- C4551958
- •
- Disease or Syndrome
Myopathy, lactic acidosis, and sideroblastic anemia (MLASA) is a rare autosomal recessive oxidative phosphorylation disorder specific to skeletal muscle and bone marrow (Bykhovskaya et al., 2004).
Genetic Heterogeneity of Myopathy, Lactic Acidosis, and Sideroblastic Anemia
MLASA2 (613561) is caused by mutation in the YARS2 gene (610957) on chromosome 12p11. MLASA3 (500011) is caused by heteroplasmic mutation in the mitochondrially-encoded MTATP6 gene (516060).
Proteasome-associated autoinflammatory syndrome 1- MedGen UID:
- 1648310
- •Concept ID:
- C4746851
- •
- Disease or Syndrome
Proteasome-associated autoinflammatory syndrome-1 (PRAAS1) is an autosomal recessive disorder characterized by early childhood onset of annular erythematous plaques on the face and extremities with subsequent development of partial lipodystrophy and laboratory evidence of immune dysregulation. More variable features include recurrent fever, severe joint contractures, muscle weakness and atrophy, hepatosplenomegaly, basal ganglia calcifications, and microcytic anemia (summary by Agarwal et al., 2010; Kitamura et al., 2011; Arima et al., 2011).
This disorder encompasses Nakajo-Nishimura syndrome (NKJO); joint contractures, muscular atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP syndrome); and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE). Among Japanese patients, this disorder is best described as Nakajo-Nishimura syndrome, since both Nakajo (1939) and Nishimura et al. (1950) contributed to the original phenotypic descriptions.
Genetic Heterogeneity of Proteasome-Associated Autoinflammatory Syndrome
See also PRAAS2 (618048), caused by mutation in the POMP gene (613386) on chromosome 13q12; PRAAS3 (617591), caused by mutation in the PSMB4 gene (602177) on chromosome 1q21; PRAAS4 (619183), caused by mutation in the PSMG2 gene (609702) on chromosome 18p11; PRAAS5 (619175), caused by mutation in the PSMB10 gene (176847) on chromosome 16q22; and PRAAS6 (620796), caused by mutation in the PSMB9 gene (177045) on chromosome 6p21.
Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia- MedGen UID:
- 1676579
- •Concept ID:
- C5193104
- •
- Disease or Syndrome
Early-onset neurodegeneration with choreoathetoid movements and microcytic anemia (NDCAMA) is an autosomal recessive disorder characterized by severe psychomotor developmental abnormalities, abnormal movements, and functional iron deficiency (Costain et al., 2019).
Mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy- MedGen UID:
- 1679560
- •Concept ID:
- C5193223
- •
- Disease or Syndrome
Episodic mitochondrial myopathy with or without optic atrophy and reversible leukoencephalopathy (MEOAL) is an autosomal recessive neuromuscular disorder characterized mainly by childhood onset of progressive muscle weakness and exercise intolerance. Patients have episodic exacerbation, which may be associated with increased serum creatine kinase or lactic acid. Additional more variable features may include optic atrophy, reversible leukoencephalopathy, and later onset of a sensorimotor polyneuropathy. The disorder results from impaired formation of Fe-S clusters, which are essential cofactors for proper mitochondrial function (summary by Gurgel-Giannetti et al., 2018)
Triokinase and FMN cyclase deficiency syndrome- MedGen UID:
- 1710207
- •Concept ID:
- C5394125
- •
- Disease or Syndrome
Triokinase and FMN cyclase deficiency syndrome (TKFCD) is a multisystem disease with marked clinical variability, even intrafamilially. In addition to cataract and developmental delay of variable severity, other features may include liver dysfunction, microcytic anemia, and cerebellar hypoplasia. Fatal cardiomyopathy with lactic acidosis has been observed (Wortmann et al., 2020).
Mitochondrial DNA depletion syndrome 18- MedGen UID:
- 1713890
- •Concept ID:
- C5394140
- •
- Disease or Syndrome
Mitochondrial DNA depletion syndrome-18 (MTDPS18) is an autosomal recessive neuromuscular disorder characterized by early-onset progressive weakness and atrophy of the distal limb muscles, resulting in loss of ambulation as well as atrophy of the intrinsic hand muscles with clawed hands. Affected individuals may also develop scoliosis and have hypo- or hyperreflexia and decreased pulmonary vital capacity. Examination of skeletal muscle shows neurogenic atrophy and combined mitochondrial oxidative phosphorylation deficiency associated with mtDNA depletion. The clinical phenotype is reminiscent of spinal muscular atrophy (see SMA, 253300) and the metabolic profile is reminiscent of 2-aminoadipic 2-oxoadipic aciduria (AMOXAD; 204750), which is caused by mutation in the DHTKD1 gene (614984) (summary by Boczonadi et al., 2018).
For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041).
Autoinflammation with episodic fever and lymphadenopathy- MedGen UID:
- 1719052
- •Concept ID:
- C5394286
- •
- Disease or Syndrome
Autoinflammation with episodic fever and lymphadenopathy (AIEFL) is an autosomal dominant immunologic disorder characterized by onset of recurrent episodes of unexplained fever beginning in early infancy. The episodes occur in a cyclic pattern with a frequency of every week or every few weeks and a duration of several days. Patients have accompanying lymphadenopathy, and some may have hepatosplenomegaly. Rash and genital ulcers are not observed. Patient serum shows increased levels of inflammatory cytokines and chemokines, including IL6 (147620) and TNF (191160), consistent with abnormal activation of the innate inflammatory system. Treatment with anti-IL6R (147880) antibodies may result in clinical improvement (summary by Lalaoui et al., 2020).
Mitochondrial DNA depletion syndrome 19- MedGen UID:
- 1770258
- •Concept ID:
- C5436514
- •
- Disease or Syndrome
Rajab interstitial lung disease with brain calcifications 2- MedGen UID:
- 1770895
- •Concept ID:
- C5436603
- •
- Disease or Syndrome
Rajab interstitial lung disease with brain calcifications-2 (RILDBC2) is an autosomal recessive disorder characterized by growth delay, interstitial lung disease, liver disease, and abnormal brain MRI findings, including brain calcifications and periventricular cysts (Krenke et al., 2019).
For a discussion of genetic heterogeneity of RILDBC, see RILDBC1 (613658).
Congenital disorder of glycosylation, type IIw- MedGen UID:
- 1794196
- •Concept ID:
- C5561986
- •
- Disease or Syndrome
Congenital disorder of glycosylation type IIw (CDG2W) is an autosomal dominant metabolic disorder characterized by liver dysfunction, coagulation deficiencies, and profound abnormalities in N-glycosylation of serum specific proteins. All reported patients carry the same mutation (602671.0017) (summary by Ng et al., 2021).
For an overview of congenital disorders of glycosylation, see CDG1A (212065) and CDG2A (212066).
Immunodeficiency 94 with autoinflammation and dysmorphic facies- MedGen UID:
- 1802872
- •Concept ID:
- C5676918
- •
- Disease or Syndrome
Immunodeficiency-94 with autoinflammation and dysmorphic facies (IMD94) is a systemic immunologic disorder with onset in early infancy. Primary features include lymphadenopathy, autoinflammation, immunodeficiency with hypogammaglobulinemia, and dysmorphic facial features. Intellectual development is normal and serum IgE is not elevated. The disease results from constitutive activation of the IL6 signaling cascade, resulting in immune dysregulation and a hyperinflammatory state (summary by Materna-Kiryluk et al., 2021).