GNPTAB c.2404C > T nonsense mutation in a patient with mucolipidosis III alpha/beta: a case report.

BACKGROUND: Mucolipidosis alpha/beta is an inborn error of metabolism characterized by deficiency of GlcNAc-1-phosphotransferase, in which essential alpha/beta subunits are encoded by the GNPTAB gene. The autosomal recessive condition is due to disruptions of hydrolase mannose 6-phosphate marker generation, defective lysosomal targeting and subsequent intracellular accumulation of non-degraded material. Clinical severity depends on residual GlcNAc-1-phosphotransferase activity, which distinguishes between the milder type III disease and the severe, neonatal onset type II disease. CASE PRESENTATION: We report the clinical, biochemical and genetic diagnosis of mucolipidosis III alpha/beta in a two-year-old Chinese boy who initially presented with poor weight gain, microcephaly and increased tone. He was confirmed to harbor the common splice site mutation c.2715 + 1G > A and the nonsense variant c.2404C > T (p.Q802*). Clinically, the patient had multiple phenotypic features typical of mucopolysaccharidosis including joint contractures, coarse facial features, kypho-lordosis, pectus carinatum and umbilical hernia. However, the relatively mild developmental delay compared to severe type I and type II mucopolysaccharidosis and the absence of macrocephaly raised the possibility of the less commonly diagnosed mucolipidosis alpha/beta. Critical roles of lysosomal enzyme activity assay, which showed elevated α-iduronidase, iduronate sulfatase, galactose-6-sulphate sulphatase, arylsulfatase B and α-hexosaminidase activities; and genetic study, which confirmed the parental origin of both mutations, were highlighted. CONCLUSIONS: The recently reported nonsense variant c.2404C > T in the GNPTAB gene is further recognized and this contributes to the genotype-phenotype spectrum of mucolipidosis alpha/beta.

Inherited metabolic diseases in the Southern Chinese population: spectrum of diseases and estimated incidence from recurrent mutations.

Inherited metabolic diseases (IMDs) are a large group of rare genetic diseases. The spectrum and incidences of IMDs differ among populations, which has been well characterised in Caucasians but much less so in Chinese. In a setting of a University Hospital Metabolic Clinic in Hong Kong, over 100 patients with IMDs have been seen during a period of 13 years (from 1997 to 2010). The data were used to define the spectrum of diseases in the Southern Chinese population. Comparison with other populations revealed a unique spectrum of common IMDs. Furthermore, the incidence of the common IMDs was estimated by using population carrier frequencies of known recurrent mutations. Locally common diseases (their estimated incidence) include (1) glutaric aciduria type 1 (∼1/60,000), (2) multiple carboxylase deficiency (∼1/60,000), (3) primary carnitine deficiency (∼1/60,000), (4) carnitine-acylcarnitine translocase deficiency (∼1/60,000), (5) glutaric aciduria type 2 (∼1/22,500), (6) citrin deficiency (∼1/17,000), (7) tetrahydrobiopterin-deficient hyperphenylalaninaemia due to 6-pyruvoyl-tetrahydropterin synthase deficiency (∼1/60,000), (8) glycogen storage disease type 1 (∼1/150,000). In addition, ornithine carbamoyltransferase deficiency and X-linked adrenoleukodystrophy are common X-linked diseases. Findings of the disease spectrum and treatment outcome are summarised here which may be useful for clinical practice. In addition, data will also be useful for policy makers in planning of newborn screening programs and resource allocation.

Aquaporin-4 autoantibody: a neurogenic cause of anorexia and weight loss.

Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease often associated with a highly specific autoantibody, aquaporin-4 antibody. Although the classic syndrome involves the optic nerves and spinal cord, aquaporin-4 antibody has been important in defining the true spectrum of NMO, which now includes brain lesions in areas of high aquaporin-4 expression. Brainstem involvement, specifically area postrema involvement in the medulla, has been associated with intractable vomiting in some patients with NMO. We describe a 14-year-old female with positive aquaporin-4 antibody whose clinical course was dominated by severe anorexia with associated weight loss (from 68-41kg; body mass index 25.2-15.6). Magnetic resonance imaging showed lesions in the medulla, pons, and thalami. Although she had asymptomatic radiological longitudinally extensive transverse myelitis, she never had symptoms or signs referable to the spinal cord or the optic nerves. We propose that anorexia and weight loss should be considered part of the NMO spectrum, probably related to area postrema involvement.