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Keywords3-methylglutaconyl-CoA Hydratase Costeff Syndrome Primary Immunodeficiency Diseases Congenital Neutropenia Leucine Degradation
3-methylglutaconic aciduria (3-MGA-uria) is a nonspecific biochemical finding related with a group of inborn errors of metabolism, particularly mitochondrial disorders. 3-MGA is a branched-chain organic acid and intermediate of leucine degradation and the mevalonate shunt pathway. The clinical features of the 3-MGA-uria syndromes are varied and are classified into five types, each with substantial heterogeneity. In all types, with the exception of 3-MGA-uria type I, the activities of 3-methylglutaconyl-CoA hydratase and other enzymes of leucine degradation are normal, and the 3-MGA-uria is considered secondary to defects in phospholipid remodeling or integrity of mitochondrial membranes, leading to electron transport chain dysfunction. 3-MGA-uria type I is an inborn error of leucine metabolism, caused by variants in AUH. AUH encodes 3-methylglutaconyl-CoA hydratase, which catalyzes the fifth step of leucine catabolism, whereby 3-methylglutaconyl-CoA is converted to 3-hydroxy-3-methylglutaryl-coenzyme A (Saunders et al. 2015; Wortmann et al. 2015).
3-MGA-uria type II, or Barth syndrome, is an X-linked recessive disorder caused by variants in TAZ, which encodes tafazzin, a cardiolipin transacylase in the inner mitochondrial membrane. 3-MGA-uria type III, or Costeff syndrome, is caused by variants in OPA3. Type V is caused by variants in DNAJC19, which encodes a mitochondrial cochaperone. DNAJC19 forms a complex with prohibitins (PHB) and lipid scaffolds in the inner membrane of the mitochondria that is necessary for mitochondrial morphogenesis, neuronal survival, and phospholipid remodeling. 3-MGA-uria type IV, the “unclassified type,” includes all other forms of 3-MGA-uria with normal 3-methylglutaconyl-CoA hydratase enzyme activity. A diagnosis of 3-MGA-uria type IV is complicated by the large number of implicated genes, including those involved in mitochondrial DNA depletion syndromes, mitochondrial DNA deletion syndromes, MELAS, Smith-Lemli-Opitz syndrome, and glycogen storage disease type 1b. Recently, two more types were added, type VI, MEGDEL syndrome, caused by mutations in SERAC1 and related with deafness and dystonia, and more recently, type VII associated with 3-MGA-uria, cataracts, neurological involvement, and neutropenia (MEGCANN) caused by homozygous or compound heterozygous mutation in the CLPB gene (Capo-Chichi et al. 2016; Kambus et al. 2015; Wortmann et al. 2015).
In this chapter we will discuss the disease caused by mutations in the gene CLPB, which codes for a member of the family of ATPases associated with various cellular activities (AAA(+) proteins) whose function remains unknown, due to the presence of severe congenital neutropenia in most cases associated with primary immunodeficiency diseases and recurrent infections.
The first description of CLPB-mutated patients described 14 affected individuals with variable phenotype from mild presentation including cataracts and neutropenia but no neurological involvement or infections to severe phenotype associated with neonatal or prenatal onset of neurological disease (progressive brain atrophy, absence of development, movement disorder, seizures), severe neutropenia with progression into leukemia, and death in the first months of life. In this cohort, patients presented intellectual disability/developmental delay (12/14 individuals investigated), congenital neutropenia (10/14), brain atrophy (7/9), microcephaly (7/12), movement disorder (7/13), cataracts (5/10), and 3-MGA-uria (12/12 individuals) (Wortmann et al. 2015). Most affected individuals suffered regularly from serious, often life-threatening, infections. Subsequently, 12 more patients were published adding different levels of neurological impairment and also nephrocalcinosis, cardiomyopathy, and facial dysmorphisms (Capo-Chichi et al. 2015; Kanabus et al. 2015; Kykim et al. 2015; Saunders et al. 2015).
Clinical diagnosis of MEGCANN should be suspected in the presence of congenital cataracts and neurological involvement. All individuals had consistent and significant excretion of 3-MGA in their urine, amounting to 2–15 times over the limit of the reference range. Most of them demonstrated neutropenia ranging from moderate to severe, and others presented the neutropenia following infectious diseases. The bone marrow examination showed different alterations including a maturation arrest at the stage of the promyelocyte and an absence of mature neutrophils in the bone marrow of individuals. The presence of clinical manifestation and laboratorial alterations suggests that the disease and the genetic evaluation can confirm the diagnosis (Capo-Chichi et al. 2015).
Treatment and Prognosis
Apart from supportive therapy and neurologic medications, there are no specific therapeutic options for these affected patients. Neutropenia generally responds to G-CSF treatment; most of the patients in the case series also received continuous antibiotics and antimycotics. There is no enough data concerning the development of hematologic malignancies in the follow-up; in these initial cases, two siblings not treated with G-CSF progressed one to an acute myeloid leukemia and another to a myelodysplastic syndrome/preleukemia; both died shortly after these diagnoses.
According the publications, the oldest affected patient alive is 18 years old, presenting a mild diagnosis, and most of them died early in life due to the severity of disease.