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McArdle disease is the most common non-lysosomal glycogenosis and have classically onset in childhood with exercise-induced pain. Fixed weakness can manifests from around fifty years of age but is typically mild and located around the shoulder girdle. We describe a 61year old man with exercise-induced pain from childhood who was referred to us due to 5years progressive muscle wasting and elevated creatine kinase to 4000U/l. On investigation he was severely atrophic and weak in his shoulder girdle and the entire paraspinal musculature. MRI confirmed that the paraspinal musculature was all converted to fat. Muscle biopsy was myopathic with negative myophosphorylase stain and multiple large vacuoles with glycogen. A non-ischemic forearm exercise test showed a small decrease in lactate together with an exaggerated ammonium elevation. Genetic testing revealed two previously described mutations in the PYGM gene verifying the suspicion of McArdle disease. This very unusual presentation of McArdle disease demonstrates that these patients can have pronounced wasting of paraspinal musculature. We suspect that this is related to the unusual high amount of glycogen vacuoles and stress the importance of including McArdle disease in the differential diagnose of axial myopathy. [Copyright &y& Elsevier]

Abstract: Fabry''s disease is an X-linked disorder due to mutations in the GLA gene encoding the lysosomal enzyme alpha-galactosidase A. Clinically, most patients present with the “classical” form, though “variant” forms with inaugural or preminent heart or kidney involvement have been described. Heterozygous women are most often symptomatic though generally less severely affected than men. We performed mutation analysis in 170 patients from 65 families and identified 55 different mutations. Our results confirm the wide molecular heterogeneity at this locus. Molecular study allows to confirm the diagnosis in male patients and the reliable diagnosis of heterozygous females in the family as biochemical tests (alpha-galactosidase A activity and urinary Gb3 study) can be normal. However, in a few cases in which the index case is a female, it may remain difficult in the absence of an extensive familial study, to confirm (identification of a new missense the pathogenicity of which is unknown) or rule out (no gene alteration found) an heterozygote. Generally, genotype/phenotype correlations remain difficult as only a few mutations are more frequent. Furthermore, variations of the phenotype, even within the same family, suggest that other factors (genetic and epigenetic) could influence disease progression. [Copyright &y& Elsevier]

Abstract: Globotriaosylceramide (Gb3) has been measured in urine of 35 male hemizygotes and 66 female heterozygotes for Fabry disease (FD). In males, Gb3 measurement allows to confirm the diagnosis which is based on deficient α-galactosidase A (α-Gal A) activity in leukocytes. Our results show that hemizygotes for classic FD have increased Gb3 and C24/C18 isoforms ratio. Hemizygotes for FD variants have slightly elevated or normal Gb3 and/or C24/C18 ratio. These variants often have a residual α-Gal A activity, and milder clinical signs. In females, urinary Gb3 is more informative than α-Gal A activity in leukocytes. Our study shows that urinary Gb3 (measurement and C24/C18 ratio) allows the diagnosis of 92 % of classical FD heterozygotes, and is often normal in variant FD heterozygotes. The diagnosis of FD heterozygote cannot be completely excluded even if urinary Gb3 and α-Gal A in leukocytes are normal. Urinary Gb3 can be used for therapeutic follow-up (enzyme replacement therapy) when increased. [ABSTRACT FROM AUTHOR]

Summary: Inherited metabolic diseases are mostly due to enzyme deficiency in one of numerous metabolic pathways, leading to absence of a compound downstream from and the accumulation of a compound upstream from the deficient metabolite(s). Diseases of intoxication by proteins (aminoacidopathies, organic acidurias, urea cycle defects) and by sugars (galactosemia, fructosemia) usually do not give prenatal symptoms since mothers protect their fetuses from pathological metabolite accumulation. A well-known exception is hypoplasia of corpus callosum, as is sometimes observed in nonketotic hyperglycinemia and sulfite oxidase deficiency. Conversely, women with phenylketonuria “poison” their fetus if they are not treated (spontaneous abortions, intrauterine growth restriction [IUGR], cardiac malformations, and brain disease). Amino acid synthesis defects can lead to prenatal symptoms: microcephaly in serine deficiency (detectable by amino acid analysis in fetal cord blood), and brain malformations in glutamine synthetase deficiency. Impaired folate metabolism is involved in a large fraction of neurodevelopmental defects referred to as spina bifida, yet the underlying genetic component(s) are largely unknown. Energy metabolism diseases caused by defects in the synthesis or utilization of relevant metabolites lead to organ dysfunctions or malformations, but prenatal diagnosis is usually impossible unless genetic analysis can rely on a previously affected child in the family. A somewhat intermediate condition is defects of mitochondrial beta-oxidation of fatty acids, as they may sometimes be symptomatic prenatally (notably the HELLP syndrome or other presentations), and in this case, organic acid and acylcarnitine analysis in amniotic fluid can be informative in the absence of an index case. In contrast, complex molecule diseases commonly give prenatal symptoms that may permit the diagnosis even in the absence of index cases: hydrops fetalis and skeletal anomalies in lysosomal storage diseases, hydrops fetalis in congenital disorders of glycosylation (CDG) and transaldolase deficiency, brain malformations in O-glycosylation defects, brain malformations, kidney cysts and skeletal anomalies in peroxysomal diseases (Zellweger syndrome), syndactyly, genitalia malformations, and IUGR in Smith-Lemli-Opitz (SLO) syndrome. Although many metabolic disorders show biochemical abnormalities during fetal development that are informative for prenatal diagnosis, only a fraction of them are clinically/sonographically symptomatic before birth, thus allowing for prenatal diagnosis in the absence of an index case, i.e., serine deficiency, some fatty acid beta-oxidation defects, transaldolase deficiency, lysosomal diseases, CDG, Zellweger syndrome, and SLO syndrome. [Copyright &y& Elsevier]

La maladie de Pompe est une maladie lysosomale secondaire à un déficit variable en maltase acide. Le déficit musculaire et la cardiomyopathie sévère sont les signes principaux de la forme infantile classique. Des formes «trompeuses» se révèlent à tout age font l’objet de cette étude d’une fratrie. L’aîné présente dès 2 mois une hypotonie avec décalage moteur modéré ; à 18 mois une hépatomégalie avec hyper-Ckémie. Dans les 3 ans, installation progressive d’une viscéromégalie, d’un syndrome myopathique, d’une cardiomyopathie modérée, conduisant à une dépendance avec ventilation sur trachéotomie. L’absence d’activité résiduelle de maltase acide dans les fibroblastes confirme le diagnostic de maladie de Pompe peu avant le décès à 5 ans. À 2 mois le cadet présente un décalage moteur ; à 21 mois une hépatomégalie avec CPK à 470 UI/l sans atteinte cardiaque. L’étude enzymatique et moléculaire confirme le diagnostic de maladie de Pompe. Une enzymothérapie est instaurée à 2,5 ans avec une évolution très favorable sur 2 ans. Des signes discrets et peu spécifiques les premiers mois de vie (hypotonie, décalage postural, hépatomégalie) imposent un dosage des CK et un dosage de la maltase acide sur papier buvard. Du diagnostic précoce dépend l’efficacité de l’enzymothérapie. [ABSTRACT FROM AUTHOR]