3-Methylglutaconic Aciduria, Type V

A number sign (#) is used with this entry because 3-methylglutaconic aciduria type V (MGCA5), also called dilated cardiomyopathy with ataxia, is caused by homozygous mutation in the DNAJC19 gene (608977) on chromosome 3q26.

Description

3-Methylglutaconic aciduria type V is an autosomal recessive disorder characterized by the onset of dilated or noncompaction cardiomyopathy in infancy or early childhood. Many patients die of cardiac failure. Other features include microcytic anemia, growth retardation, mild ataxia, mild muscle weakness, genital anomalies in males, and increased urinary excretion of 3-methylglutaconic acid. Some patients may have optic atrophy or delayed psychomotor development (summary by Davey et al., 2006 and Ojala et al., 2012).

For a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA type I (250950).

Clinical Features

Davey et al. (2006) reported 18 patients with dilated cardiomyopathy and ataxia from 11 consanguineous Canadian Dariusleut Hutterite families. Affected individuals had severe, early-onset dilated cardiomyopathy (sometimes accompanied by long QT syndrome), prenatal or postnatal growth failure, and cerebellar ataxia causing significant motor delays. Genital anomalies secondary to testicular dysgenesis were seen in 9 of 11 male patients, ranging from isolated cryptorchidism to severe perineal hypospadias. Affected patients consistently showed 5- to 10-fold increases in both plasma and urine 3-methylglutaconic acid and 3-methylglutaric acid. Additional features included normochromic microcytic anemia in 12 patients, mild to borderline nonprogressive mental retardation in 10, a mild increase in hepatic enzymes with microvesicular hepatic steatosis in 5, and optic atrophy in 4. The onset of cardiomyopathy was always before the age of 3 years, and over 70% of affected individuals died from either progressive cardiac failure or sudden cardiac death.

Sparkes et al. (2007) retrospectively reviewed the clinical course of 17 Hutterite patients reported by Davey et al. (2006). Of the 17, 13 (76%) had an echocardiographic or pathologic diagnosis of dilated cardiomyopathy with a mean age at onset of 12 months (range, 1-36 months). The cardiomyopathy was characterized by increased left ventricular end diastolic dimensions, mural thinning, and poor systolic function, with mild to severe global hypokinesia. Ten children died of congestive heart failure or arrhythmias at a mean age of 22 months (range, 4-48 months). Two males, aged 13 and 23 years, had resolution of the cardiomyopathy with only mild residual mitral regurgitation. Another male patient had persistent but clinically stable mild cardiomyopathy at age 15 years. Four patients did not develop cardiomyopathy. Electrocardiographic findings of 13 patients showed a prolonged QT interval in 8 patients, both in the presence (6) and absence (2) of dilated cardiomyopathy. One of the patients with isolated long QT died suddenly at age 14 months.

Ojala et al. (2012) reported 2 Finnish brothers, born of unrelated parents, with MGCA5. Shortly after birth, both showed growth retardation, hypoglycemia, and microcytic anemia. Both patients developed symptomatic noncompaction cardiomyopathy with a prolonged QT interval. The older brother showed mildly delayed psychomotor development, mild ataxia, muscle weakness, and a gradual deterioration of fine motor skills. Laboratory studies showed high urinary excretion of methylglutaconic acid, mild urinary excretion of 3-methylglutarate, mildly increased urinary lactate, and a mild increase in plasma alanine aminotransferase. Muscle biopsy showed mild neutral lipid accumulation and partial deficiency of mitochondrial respiratory chain function. The older brother was doing well at age 49 months. The younger brother had cryptorchidism and chorda penis. Urinary organic acid analysis was normal in this patient at age 10 months. Despite intensive treatment, he died of cardiac failure at age 13 months. Postmortem examination showed a mildly atrophic brainstem with reduction of neuronal density in the cerebellum, as well as a dilated and noncompacted cardiac left ventricle.

Inheritance

The transmission pattern of MGCA5 in the family reported by Davey et al. (2006) was consistent with autosomal recessive inheritance.

Mapping

Davey et al. (2006) performed a genome scan using homozygosity mapping in 5 severely affected Canadian Dariusleut Hutterite patients from consanguineous families; fine mapping of candidate regions identified a 23.9-cM disease-associated haplotype on chromosome 3q26.2-q27.3 between markers D3S1282 and D3S1262. Genotyping of an additional 10 affected individuals and their unaffected family members narrowed the critical region to 2.2 Mb between D3S3603 and D3S2314 on 3q26.33.

Molecular Genetics

Davey et al. (2006) sequenced candidate genes in patients with dilated cardiomyopathy and ataxia from a Canadian Dariusleut Hutterite population and identified homozygosity for a splice site mutation in the DNAJC19 gene (608977.0001) in all 16 patients for whom DNA samples were available. Unaffected parents were heterozygous for the mutation.

In 2 Finnish brothers with MGCA5, Ojala et al. (2012) identified a homozygous truncating mutation in the DNAJC19 gene (608977.0002). The unaffected parents were heterozygous for the mutation.

Population Genetics

In a carrier screening of autosomal recessive mutations involving 1,644 Schmiedeleut (S-leut) Hutterites in the United States, Chong et al. (2012) identified the DNAJC19 dilated cardiomyopathy and ataxia mutation IVS3-1G-C (rs137854888, 608977.0001) in heterozygous state in 42 individuals among 1,504 screened and in homozygous state in none, for a carrier frequency of 0.028 (1 in 36). This is a private mutation in the Hutterite population.