Three inborn errors of galactose metabolism are known, one for each step in the Leloir pathway of galactose conversion to glucose. The first, galactokinase deficiency, is discovered either through newborn screening for hypergalactosemia, or by the chance finding of reducing substance in urine, or by selective urine screening for galactose in infants or older persons examined for nuclear cataracts. In the undiagnosed newborn drinking milk, cataracts develop insidiously within a few weeks as the only clinical manifestation. Galactose-galactitol-glucose diabetes is the only chemical sign. Diagnosis is made by enzyme assay on blood cells or fibroblasts. For treatment, milk and milk products are eliminated from the diet. In transferase deficiency or galactosemia, the second step in the Leloir pathway is blocked. In most developed countries, this defect is discovered through newborn screening, and the more serious clinical symptoms are avoided by prompt treatment. Infants who remain undiagnosed develop symptoms and signs of liver and kidney failure and succumb to sepsis. Survivors develop cataracts and mental impairment. Diagnosis is suggested by the presence of reducing substance in the urine of the fed newborn, and it is made by enzyme assay on blood cells, a liver biopsy specimen, or fibroblasts. Lifelong exclusion of all galactose from the diet is stipulated, but difficult to achieve. Partial transferase deficiency is more frequent than the complete defect. It is treated by a less-than-complete removal of dietary galactose, usually restricted to the first few months of life. The third defect of the Leloir pathway, epimerase deficiency, occurs in both a benign mild form and a severe and crippling form. Both are discovered through newborn screening, using methods sensitive to galactose-1-phosphate and are diagnosed by enzyme assay on blood cells or fibroblasts. Infants with the mild form do not seem to require treatment. The two documented severe cases showed clinical features reminiscent of untreated galactosemia; their dietary treatment proved difficult and unsatisfactory.

Disorders of Galactose Metabolism

Objective: Centronuclear myopathy (CNM) is a rare congenital myopathy characterized by prominence of central nuclei on muscle biopsy. CNM has been associated with mutations in MTM1, DNM2, and BIN1 but many cases remain genetically unresolved. RYR1 encodes the principal sarcoplasmic reticulum calcium release channel and has been implicated in various congenital myopathies. We investigated whether RYR1 mutations cause CNM. Methods: We sequenced the entire RYR1 coding sequence in 24 patients with a diagnosis of CNM from South Africa (n ¼ 14) and Europe (n ¼ 10) and identified mutations in 17 patients. The most common genotypes featured compound heterozygosity for RYR1 missense mutations and mutations resulting in reduced protein expression, including intronic splice site and frameshift mutations. Results: The high incidence in South African patients (n ¼ 12/14) in conjunction with recurrent RYR1 mutations associated with common haplotypes suggested the presence of founder effects. In addition to central nuclei, prominent histopathological findings included (often multiple) internalized nuclei and t ype 1f iber predominance and hypotrophy with relative type 2 hypertrophy. Although cores were not typically seen on oxidative stains, electron microscopy revealed subtle abnormalities in most cases. External ophthalmoplegia, proximal weakness, and bulbar involvement were prominent clinical findings. Interpretation: Our findings expand the range of RYR1-related phenotypes and suggest RYR1 mutations as a common cause of congenital myopathies with central nuclei. Corresponding to recent observations in X-linked CNM, these findings indicate disturbed assembly and/or malfunction of the excitation-contraction machinery as a key mechanism in CNM and related myopathies. ANN NEUROL 2010;68:717–726

https://deepblue.lib.umich.edu/bitstream/handle/2027.42/78229/22119_ftp.pdf?sequence=1

RYR1 mutations are a common cause of congenital myopathies with central nuclei

https://www.pedneur.com/article/S0887-8994(05)00162-1/pdf

An Updated Review of the Long-Term Neurological Effects of Galactosemia

Without intervention, classic galactosemia is a potentially fatal disorder in infancy. With the benefit of early diagnosis and dietary restriction of galactose, the acute sequelae of classic galactosemia can be prevented or reversed. However, despite early and lifelong dietary treatment, many galactosemic patients go on to experience serious long-term complications including cognitive disability, speech problems, neurological and/or movement disorders and, in girls and women, ovarian dysfunction. Further, there remains uncertainty surrounding what constitutes a 'best practice' for treating this disorder. To explore the extent and implications of this uncertainty, we conducted a small but global survey of healthcare providers who follow patients with classic galactosemia, seeking to compare established protocols for diagnosis, intervention, and follow-up, as well as the outcomes and outcome frequencies seen in the patient populations cared for by these providers. We received 13 survey responses representing five continents and 11 countries. Respondents underscored disparities in approaches to diagnosis, management and follow-up care. Notably, we saw no clear relationship between differing approaches to care and long-term outcomes in the populations studied. Negative outcomes occurred in the majority of cases regardless of when treatment was initiated, how tightly galactose intake was restricted, or how closely patients were monitored. We document here what is, to our knowledge, the first global comparison of healthcare approaches to classic galactosemia. These data reinforce the idea that there is currently no one best practice for treating patients with classic galactosemia, and underscore the need for more extensive and statistically powerful comparative studies to reveal potential positive or negative impacts of differing approaches.

/pdf/diversity-of-approaches-to-classic-galactosemia-around-the-5apmryhr5d.pdf

Diversity of approaches to classic galactosemia around the world: a comparison of diagnosis, intervention, and outcomes

https://pedclerk.uchicago.edu/sites/pedclerk.uchicago.edu/files/uploads/BerryGalactosemiaEmergency.pdf

Galactosemia: when is it a newborn screening emergency?

The objective of this study was to document the clinical, laboratory and genetic features of galactosemia in patients from the Cape Town metropolitan region. Diagnoses were based on thin layer chromatography for galactosuria/galactosemia and assays of erythrocyte galactose-1-phosphate uridyltransferase (GALT) and galactokinase activities. Patients were screened for the common S135L and Q188R transferase gene mutations, using PCR-based assays. Screening for the S135L mutation in black newborns was used to estimate the carrier rate for galactosemia in black South Africans. A positive diagnosis of galactosemia was made in 17 patients between the years 1980 to 2001. All had very low or absent galactose-1-phosphate uridyltransferase (GALT) activity, and normal galactokinase levels. The mean age at diagnosis was 5.1 months (range 4 days to 6.5 months). A review of 9 patients showed that hepatomegaly (9/9), and splenomegaly, failure to thrive, developmental delay, bilateral cataracts (6/9) were the most frequent features at diagnosis. Six had conjugated hyperbilirubinemia. Four experienced invasive E. coli infection before diagnosis. Ten patients were submitted to DNA analysis. All 4 black patients and 2 of mixed extraction were homozygous for the S135L allele, while all 3 white patients were homozygous for the Q188R allele. The remaining patient of mixed extraction was heterozygous for the Q188R allele. The estimated carrier frequency of the S135L mutation in 725 healthy black newborns was 1/60. In the absence of newborn screening the delay in diagnosis is most often unacceptably long. Also, carrier frequency data predict a galactosemia incidence of approximately 1/14 400 for black newborns in the Cape Metropole, which is much higher than the current detection rate. It is thus likely that many patients go undetected.

/pdf/the-clinical-and-molecular-spectrum-of-galactosemia-in-595yn2gbje.pdf

The clinical and molecular spectrum of galactosemia in patients from the Cape Town region of South Africa

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The clinical and molecular spectrum of galactosemia in patients from the Cape Town region of South Africa