Insights into the Pathophysiology of Infertility in Females with Classical Galactosaemia.

Classical galactosaemia (CG) (OMIM 230400) is a rare inborn error of galactose metabolism caused by the deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT, EC 2.7.7.12). Primary ovarian insufficiency (POI) is the most common long-term complication experienced by females with CG, presenting with hypergonadotrophic hypoestrogenic infertility affecting at least 80% of females despite new-born screening and lifelong galactose dietary restriction. In this review, we describe the hypothesized pathophysiology of POI from CG, implications of timing of the ovarian dysfunction, and the new horizons and future prospects for treatments and fertility preservation.

The genetic and biochemical basis of trimethylaminuria in an Irish cohort.

BACKGROUND: Inherited trimethylaminuria (TMAU), a rare genetic disorder of hepatic metabolism of trimethylamine (TMA) causing excessive accumulation of malodorous trimethylamine (TMA), is a socially distressing disorder. Diagnosis is made by biochemical analysis of urine, with the calculation of flavin monooxygenase trimethylamine conversion capacity. Genetic testing, sequencing the entire coding region of the FMO3 gene has been recommended for affected individuals who convert less than 90% of the total TMA load to TMAO. METHODS: Genetic analysis was undertaken for 13 Irish patients with TMAU of varying phenotypic severity (three severe, six moderate, and four mild). RESULTS: A genetic diagnosis was made for seven patients, including for five of the nine moderate to severely affected cases. We noted the c.913G>T;p.(Glu305*) and c.458C>T;p.(Pro153Leu) mutations in this Irish population with severe TMAU which is consistent with our earlier findings in Australian and North American families of Irish and British descent.Three individuals were noted to be homozygous for the common variant haplotype c.472G>A;923A>G;p.(Glu158Lys);(Glu308Gly). We also identified three novel variants in this population, which are likely to be pathogenic: c.682G>A;p(Gly228Ser), c.694G>T:p(Asp232Tyr), and c.989G>A;p.(Gly330Glu). CONCLUSION: Urinary biochemical analysis probably remains the first line diagnostic approach to classify the various types of TMAU. FMO3 gene analysis is likely only to be informative for certain presentations of TMAU.

Metallosis mimicking a metabolic disorder: a case report.

Metalic prosthesis or occupational exposure are potential sources of systemic cobalt and chromium ion toxicity. The resultant multisystemic clinical presentation can lead to unnecessary investigations before a final etiologic diagnosis is made; with an average delay of a year or more commonly noted. A 58-year old man presented with cardiomyopathy, pericardial effusion, polycytaemia, polyneuropathy, visual impairment, sudden hearing loss and hypothyroidism over a 2-year period post a metal-on-polyethylene hip replacement surgery. Biochemistry test results showed serum lactate of 3.8 mmol/L (0.5-2.2 mmol/L). Urine organic acid screen showed mild increases in excretion of tricarboxylic acid cycle intermediates and 2-ethylhydracryllate; suggestive of primary or secondary mitochondrial dysfunction. There were also slight increases in excretion of 4-hydroxyphenyllactate and 4-hydroxyphenylpyruvate suggestive of liver dysfunction. Acylcarnitine profile showed slight increase in hydroxybutyrylcarnitine and tetradeceneoylcarnitine that may reflect ketosis. In view of his clinical presentation and abnormal metabolic investigations, the initial working diagnosis was mitochondrial disease. Subsequently, patient presented with hip pain, and radiologic and imaging studies revealed high density collections lateral to the right proximal part of the femur, and medial to the right ilium with signal changes suggestive of metallic content. This prompted toxicology screen which revealed elevated plasma cobalt concentration (903.32 µg/L; reference range: 0.1-0.4) and chromium (71.32 µg/L; <0.5). Six months post right hip prosthesis removal the concentrations have declined and was 61.72 µg/L and chromium 23.97 µg/L. Patient felt some improvement symptomatically, without evident deterioration in his vision or hearing. This case emphasises careful consideration of past medical history, in patients presenting with multisystemic disease suggestive of mitochondrial dysfunction, and potential causality related to exposure to toxic agents. In retrospect, the absence of a family history could be viewed as a pertinent negative finding. Not uncommonly, specialist focus on their favored system and may not search for a unifying diagnosis. It is likely further delays in diagnosis would have occurred had the patient not developed hip pains, and ultimately referred to the orthopedic surgeons more familiar with similar cases.