Paula and Bobby
Parents of Lillie
3-methylglutaconic aciduria - type II
What is 3-methylglutaconic aciduria - type II?
3-methylglutaconic aciduria - type II is a rare disease. It is also known as Barth syndrome Familial primary endocardial fibroelastosis X-linked endocardial fibrosis.
There have been several pedigrees in which X-linked inheritance of endocardial fibroelastosis is a possibility. Hodgson et al., (1987) reported a convincing family. Some of the males in that family died rapidly soon after birth, having presented with peripheral oedema and ascites. The symptomatology is often failure to thrive and cardiac failure and in general the X-linked type tends to be severe. Facially, the forehead is broad and tall the face is round with prominant cheeks and jaw, the ears large and the eyes deepset. These features lessen with age and a gynoid body habitus then develops (Hastings et al., 2009). It is highly likely that there are mitochondrial changes in this form, and these have been shown in at least three of the X-linked families (see also Neustein et al., 1979 and Barth et al., 1987). Neutropenia is a feature in some families. Kelley et al., (1991) studied seven affected boys from five further families and demonstrated a 3-methylglutaconic aciduria - two of Barth's original cases were also shown to have this finding, but not all patients have this (Schmidt et al., 2004). Christodoulou et al., (1994) reported six cases from four families and noted that the severity of infections tended to improve with age while short stature persisted. They also noted myopathic facies and nasal speech. A single mitochondrial phospholipid, tetralinoleoyl-cardiolipin was lacking in skeletal muscle in 8 children reported by Schlame et al., (2002). Cardiolipn deficiency in cultured fibroblasts was reported by Valianpour et al., (2002).
Bolhuis et al., (1991) showed linkage to Xq28 in the family reported by Barth et al., (1987). This finding was confirmed in an Australian family (Ades et al., 1993).
Ibel et al., (1993) reported a case with hypertrophic cardiomyopathy and multiple respiratory chain abnormalities including severe impairment of complex I and complex IV activities in skeletal muscle and complex IV activity in heart alone.
Gedeon et al., (1995) reported a large X-linked family where affected males died in infancy of dilated cardiomyopathy, but without other features of Barth syndrome. The gene mapped to Xq28 and the authors suggested that it might be allelic to Barth syndrome. Fetal cardiomyopathy and stillbirth were emphasised by Steward et al., (2010).
Bione et al (1996) reported mutations in a gene, G4.5, coding for several unique proteins, depending on differential splicing. All the mutations resulted in a stop codon. Of interest, is that families with X-linked dilated cardiomyopathy have mutations in the same gene (D'Adamo et al., 1997),
Bleyl et al., (1997) reported an X-linked pedigree where affected males had isolated noncompaction of the left ventricular myocardium. This consists of numerous prominent trebeculations in the left ventricle and is associated with endocardial fibroelastosis. Some cases in the family had neutropenia, growth retardation, and mitochondrial abnormalities consistent with Barth syndrome. The condition appeared to map to Xq28. Bleyl et al., (1997) demonstrated a mutation in the G4.5 gene in this family. This was altered in the glycine-to-arginine substitution at position 197 of the protein Digilio et al., (1999) point out that not all cases of noncompaction of the left ventricular myocardium are X-linked. They report three affected females including one from a consanguineous pedigree. Pauli et al., (1999) reported a girl with ventricular noncompaction who had a 5q35.1-35.3 deletion. However, note that Sasse-Klaassen et al., (2003) studied 25 adults with INVM and did not find G4.5 mutations in any. In some cases there was an autosomal dominant family history.
D'Adamo et al., (1997) reported mutations in the G4.5 gene in families with X-linked dilated cardiomyopathy. Johnston et al., (1997) could find no correlation between phenotype and genotype for different mutations.
Orstavik et al., (1998) provided evidence for skewed X inactivation in female carriers.
De Kremer et al., (2001) studied a 4.5 year old male with a presentation similar to Barth's syndrome. There was severe failure to thrive from early infancy, delayed motor milestones, muscle weakness, and dilated cardiomyopathy. There were persistently elevated urinary levels of 3-methylglutaconic and 2-ethylhydracrylic acids and low levels of cholesterol. An A3243G mutation in mitochondrial DNA was demonstrated.
* This information is courtesy of the L M D.
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What gene changes cause 3-methylglutaconic aciduria - type II?
The syndrome is inherited in the following inheritance pattern/s:
X-Linked Recessive - Syndromes inherited in an X-linked recessive pattern generally only affect males. Males only have one X chromosome, and so one copy of a gene mutation on it causes the syndrome. Females, with two X chromosomes, only one of which will be mutated, are not likely to be affected.
In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation that occurs during the reproductive process.
The syndrome can be caused by mutations in the following gene/s location/s:
What are the main symptoms of 3-methylglutaconic aciduria - type II?
The typical symptoms of the syndrome are:
How does someone get tested for 3-methylglutaconic aciduria - type II?
The initial testing for 3-methylglutaconic aciduria - type II can begin with facial genetic analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the type of genetic testing needed. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
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