#271980
ICD+
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| SUCCINIC SEMIALDEHYDE DEHYDROGENASE DEFICIENCY | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| SSADH DEFICIENCY 4-HYDROXYBUTYRIC ACIDURIA GABA METABOLIC DEFECT GAMMA-HYDROXYBUTYRIC ACIDURIA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because succinic semialdehyde dehydrogenase (SSADH) deficiency is caused by mutation in the ALDH5A1 gene (610045). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Jakobs et al. (1981) reported a patient with neurologic abnormalities and urinary excretion of gamma-hydroxybutyric acid. Gibson et al. (1983) demonstrated deficiency of the succinic semialdehyde dehydrogenase enzyme in lymphocyte lysates from 2 patients with gamma-hydroxybutyric aciduria. Enzyme activity was 9 to 13% of control values. Gibson et al. (1984) demonstrated levels of SSADH enzyme activity consistent with heterozygosity in both parents of the first reported affected child (Jakobs et al., 1981), who was the offspring of consanguineous Turkish parents. Psychomotor development was mildly retarded but ataxia was severe. He also had marked hypotonia without weakness. Follow-up at age 5 showed no progression or improvement. Increased concentrations of gamma-aminobutyric acid (GABA) were found in the urine and CSF. Haan et al. (1985) described a 3-year-old boy, born of first-cousin Maltese parents, with SSADH deficiency. Delayed development was the main feature. He did not have ataxia, oculomotor apraxia, or seizures. Roesel et al. (1987) observed this disorder in a brother and sister who also showed increased glycine excretion. Gibson et al. (1997) described differing clinical presentation of SSADH deficiency in an adolescent brother and sister from Lifu Island, New Caledonia. The 2 affected sibs were from a sibship of 7 whose parents were first cousins. The 15-year-old male had global psychomotor and intellectual retardation, functioning at the developmental level of 4 years. His sight was said to be poor, and growth was subnormal. Genitalia were underdeveloped and there were no secondary sexual characteristics. The younger female sib was more severely affected. As in the case of her brother, her eyesight was thought to be poor. At age 11, she developed tonic/clonic seizures, which were only partially controlled by valproic acid. Treatment with vigabatrin aggravated the convulsive disorder. Gibson et al. (1997) reported 23 new patients with SSADH deficiency. The most frequent clinical features included developmental delay of motor, mental, and language skills, hypotonia, seizures, hyporeflexia, ataxia, behavioral problems, and EEG abnormalities. Less common features included abnormal eye movements and psychosis in older patients. Approximately 30% of patients had normal early development and there was a wide variability in the severity of mental retardation. Chambliss et al. (1998) stated that SSADH deficiency had been identified in approximately 150 patients. Affected individuals accumulate large quantities of 2 neuroactive compounds in physiologic fluids: GABA and 4-hydroxybutyric acid (GHB). Gibson et al. (1998) provided a review of succinic semialdehyde dehydrogenase deficiency and contrasted the clinical and biochemical findings in patients with neuropharmacologic data on 4-hydroxybutyric acid accumulation in animals and humans. Pearl et al. (2003) stated that SSADH deficiency had been diagnosed in approximately 350 patients. They reported 11 additional patients and reviewed the clinical features of 51 previously reported patients. Age at diagnosis ranged from 1 to 21 years. The main clinical features included mild to moderate mental retardation, disproportionate language dysfunction, hypotonia, hyporeflexia, autistic behaviors, seizures, and hallucinations. Brain MRI of 5 patients showed symmetric increased T2 signal in the globus pallidi. Pearl et al. (2003) noted that GHB has neuroactive properties and has been used to manage cataplexy and alcohol- and opiate-withdrawal syndromes. Blasi et al. (2006) reported a female infant with SSADH deficiency confirmed by genetic analysis (see 610045.0006). She presented at age 9 months with psychomotor delay, strabismus, and generalized hypotonia. Biochemical studies showed severely decreased SSADH enzyme activity. Leuzzi et al. (2007) reported 2 Italian sibs with SSADH deficiency who developed paroxysmal exercise-induced dystonia at age 16 and 12 years, respectively. Their prior phenotypes were classic for SSADH deficiency. Treatment with vigabatrin improved the paroxysmal dystonia in both patients and also improved gait clumsiness and seizures in 1 patient. O'Rourke et al. (2010) reported a 9-month-old boy with mild global delay who presented with 'yes-yes' head bobbing. Brain imaging showed abnormal signal hyperintensities in the globus pallidus and white matter on T2-weighted MRI, and brain magnetic resonance spectroscopy (MRS) showed high lactate, consistent with SSADH deficiency. The authors suggested that increased gamma-hydroxybutyrate may affect diencephalic extrapyramidal pathways, resulting in abnormal movement. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inheritance | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Parental consanguinity and intermediate levels of SSADH enzyme in parents of affected children support autosomal recessive inheritance (Gibson et al., 1984). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Diagnosis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pearl et al. (2003) noted that standard organic acid assays commonly miss increased urinary excretion of 4-hydroxybutyric acid because it is a highly volatile compound. The authors suggested that selective ion monitoring gas chromatography-mass spectrometry for specific compounds yields more accurate results. Prenatal Diagnosis Jakobs et al. (1993) reported prenatal diagnosis of SSADH deficiency by metabolite measurement and enzyme analysis in amniotic fluid and cells. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 4 patients from 2 unrelated families with SSADH deficiency, Chambliss et al. (1998) identified homozygosity for 2 different splice site mutations in the ALD5A1 gene (610045.0001; 610045.0002). Unaffected parents and sibs were heterozygous for the mutations. Akaboshi et al. (2003) stated that the underlying mutation in SSADH deficiency had been reported in patients from 6 families worldwide and 8 different mutations were described. They reported the mutational spectrum in 48 additional unrelated patients of different geographic origin. They detected 27 novel mutations in the ALDH5A1 gene (see, e.g., 610045.0003-610045.0005). Almost all the missense mutations reduced the SSADH activity to less than 5% of the normal activity in an in vitro expression system. The findings suggested that residual protein expression is not likely to be an important factor contributing to the very large phenotypic differences observed among different families and even among sibs, suggesting that other modifying factors are of great importance in disease pathology. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Divry et al. (1983); Gibson et al. (1997); Gibson et al. (1984); Rating et al. (1982) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| REFERENCES | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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