A Nonclassical Clinical Course of Barth Syndrome

A 6-year-old boy of Roma decent, born to nonconsanguineous, healthy parents was primarily referred because of growth retardation. Auxological parameters were below the 3rd percentile after having been normal at birth. The 3rd percentile had been crossed at age 12 months, without any catch-up growth afterward. Especially, the extent of microcephaly (< 3 standard deviation) was impressive. In addition, mild generalized muscular hypotonia was present. Psychomotor development was regular. Gastrointestinal, endocrinological, and nutritional work-up revealed no explanatory pathological findings. Metabolic work-up including lactate profile, pyruvate and lactate/pyruvate ratio, urinary organic acids, plasma amino acid profile, ammonia, creatine kinase, total and free carnitine, and acylcarnitine profile was normal. Magnetic resonance imaging (MRI) of the brain and MR spectroscopy showed no pathologies. Overall, 18 months later, the patient presented with episodes of painless muscular weakness and severe exercise intolerance triggered by a febrile infection. Clinical findings included muscular weakness, hypotonia, and positive Gower’s sign in the absence of muscular atrophy.

Diagnostic work-up again revealed normal values for creatine kinase, ASAT, ALAT, and metabolic parameters. Myosonography was unremarkable. The combination of unclear muscular symptoms and persistent growth retardation prompted mitochondrial work-up. A muscle biopsy from m. rectus femoris revealed reduced activity of complex I, III, and IV in oxidative phosphorylation. Whole exome sequencing revealed the mutation c.281G>A (p.Arg94His) in the tafazzin gene (NM_000116). This mutation has been described as associated with early onset, severe Barth syndrome.¹ The diagnosis of Barth was supported by a specific pattern of fatty acid profile of cardiolipin.

Nevertheless, characteristic signs and symptoms for Barth syndrome such as cardiomyopathy, neutropenia, or 3-methylglutaconic aciduria have never been observed in the patient. At the age of 10 years, the patient shows persistent growth retardation and very mild exercise intolerance. Echocardiography and white blood cell counts as well as psychomotor development are persistently normal for age.

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References

1 Brady AN, Shehata BM, Fernhoff PM. X-linked fetal cardiomyopathy caused by a novel mutation in the TAZ gene. Prenat Diagn 2006;26(5):462–465