Maleylacetoacetate Isomerase Deficiency
A number sign (#) is used with this entry because of evidence that maleylacetoacetate isomerase deficiency (MAAID) is caused by compound heterozygous or homozygous mutation of the GSTZ1 gene (603758) on chromosome 14q24.
DescriptionDeficiency of maleylacetoacetate isomerase (MAAID) is characterized by mild elevations in succinylacetone in blood and urine, usually identified by newborn screening. Liver function and coagulation are normal. MAAID is differentiated from hepatorenal tyrosinemia (TYRSN1; 276700), which is also identified by hypersuccinylacetonemia on newborn screening but is a severe disorder with hepatic failure, renal tubulopathy, rickets, and porphyria-like neurologic crises. MAAID and TYRSN1 are caused by mutations in genes encoding the penultimate and ultimate enzymes, respectively, in the phenylalanine and tyrosine degradation pathway (summary by Yang et al., 2017).
Clinical FeaturesYang et al. (2017) reported 3 boys and 3 girls with MAAID, identified by newborn screening with mildly elevated succinylacetone (SA) by mass spectrometry on dried blood spot. Initial plasma SA level ranged from 233-1282 nmol/L (median 358 nmol/L) with an assay reference range of less than 24 nmol/L. This compares with hepatorenal tyrosinemia (TYRSN1) patients whose initial plasma SA levels ranges from 16,944 to 74,377 nmol/L (median 39,454). In urine, the SA level in benign hypersuccinylacetonemia subjects ranged from 73-4,103 micromol/mol creatinine (median 522) versus less than 34 micromol/mol creatine in controls. In TYRSN1 HT1 patients the urine SA ranged from 59,921-1,195,273 micromol/L (median 290,391). There was no overlap in laboratory values between the TYRSN1 group and the MAAID group. All individuals with benign hypersuccinylacetonemia had normal prothrombin (176930) time and international normalized ratio (PT/INR). Initial serum alpha-fetoprotein (AFP; 104150) was normal and remained within age-appropriate reference range for all 6 subjects for up to 13 years of follow-up. Plasma amino acids showed no elevation of tyrosine. There was no liver or kidney dysfunction or disease detected by imaging.
Molecular GeneticsYang et al. (2017) identified 6 individuals with MAAID. Four were homozygous for an ala150-to-val mutation (A150V; 603758.0001), 1 was compound heterozygous for a nonsense (R87X; 603758.0002) and an intronic (c.68-12G-A, 603758.0003) mutation, and in 1 patient, only 1 mutation was detected (V99M; 603758.0004).