Classical Hereditary galactosemia: findings in patients and animal models.

Classic galactosemia is a rare inborn error of metabolism that affects the metabolism of galactose, a sugar derived from milk and derivates. Classic galactosemia is caused by variants of the GALT gene, which lead to absent or misfolded forms of the ubiquitously present galactose-1-phosphate uridylyltransferase enzyme (GALT) driving galactose metabolites to accumulate, damaging cells from neurons to hepatocytes. The disease has different prevalence around the world due to different allele frequencies among populations and its symptoms range from cognitive and psychomotor impairment to hepatic, ophthalmological, and bone structural damage. The practice of newborn screening still varies among countries, dairy restriction treatment is a consensus despite advances in preclinical treatment strategies. Recent clinical studies in Duarte variant suggest dairy restriction could be reconsidered in these cases. Despite noteworthy advances in the classic galactosemia understanding, preclinical trials are still crucial to fully understand the pathophysiology of the disease and help propose new treatments. This review aims to report a comprehensive analysis of past studies and state of art research on galactosemia screening, its clinical and preclinical trials, and treatments with the goal of shedding light on this complex and multisystemic innate error of the metabolism.

Novel GALT variations and genetic spectrum in Turkish population with the correlation of genotype and phenotype.

Classic galactosemia (OMIM#230400) is an autosomal recessive inborn error of carbohydrate metabolism caused by a deficiency of the galactose-1-phosphate-uridyl-transferase enzyme encoded by the GALT gene. Even though a galactose-restricted diet efficiently resolves the acute complications, it is insufficient to prevent long-term complications regarding speech defects, intellectual functioning, premature ovarian failure, cataract, hepatomegaly, dysarthria, ataxia, and tremor. Seventy-seven patients who were genetically diagnosed with classic galactosemia were included in this cohort. Identified novel variants were classified based on their predicted effect on the GALT function. Further, potential genotype-phenotype correlations were investigated via statistical analysis. In total, 18 different sequence variants were identified, including four novels (c.200delG/p.(Arg67Profs* 19), c.533T>G/ p.(Met178Arg), c.708_709delGT/p.(Ser236Argfs* 30), c.467C>A/p.(Ser156* )). Jaundice was the most common short-term finding with 80% (61/77). Even with early diagnosis, intellectual disability is encountered with 36% (27/74) of the long-term complications. Patients with biallelic missense variants have a significantly higher prevalence of cataracts (OR: 17.9). Longitudinal observations showed attenuation of cataracts and hepatomegaly. This study has shown the GALT variation spectrum of the Turkish population with a 30-year retrospective cohort, submitting a significant contribution to the genotype/phenotype correlation in galactosemia. This study also highlights the cost-effective importance of Sanger sequencing in the diagnosis of single-gene metabolic diseases.

Transient developmental delays in infants with Duarte-2 variant galactosemia.

Duarte galactosemia is not classic galactosemia, but rather an example of biochemical variant galactosemia that results in approximately 25% residual activity of galactose-1-phosphate uridylyltransferase (GALT) enzyme. In contrast, classic galactosemia is associated with complete or near complete absence of GALT activity. While infants with classic galactosemia are placed on galactose-restricted diets to prevent the acute and long-term manifestations of their metabolic disorder, while individuals with Duarte variant galactosemia (Duarte-2 galactosemia) do not require diet therapy. The long-term complications that are seen in classic galactosemia such as cerebellar ataxia, and hypergonadotropic hypogonadism do not occur in Duarte-2 galactosemia. While Duarte galactosemia does not appear to be a metabolic disease, it may have an impact on early neurodevelopmental outcomes. This study examined developmental outcomes and the need for special services in individuals with Duarte-2 galactosemia in comparison to individuals with classic galactosemia. We performed a medical record review of individuals with GALT deficiency who were evaluated at Boston Children's Hospital and enrolled in our study of outcomes in galactosemia. This included 95 participants, 21 with Duarte-2 galactosemia and 73 with classic galactosemia. Duarte-2 participants had developmental test scores within the average range. However, 42% of subjects with Duarte-2 galactosemia had participated in early intervention and/or special education and 32% received speech therapy. Their pattern of strengths and weaknesses in cognitive/language/motor domains was similar to that noted in participants with classic galactosemia, albeit to a milder degree. The data indicate that in children with Duarte-2 variant galactosemia, the cognitive/language and motor skills were within normal limits with their cognitive/language skills developing earlier than their motor skills during their first year of life. A history of diet treatment was not related to the use of special services. These results suggest that Duarte-2 galactosemia increases the risk for early mild developmental delays irrespective of treatment history, which resolves over time, and highlights the need to further assess neurodevelopment in early infancy, in Duarte-2 galactosemia. As Duarte-2 galactosemia is not a bona fide biochemical genetic disease, we hypothesize that elements in the genomic space that include the GALT gene are responsible for a transient delay in language-related motor skills during early infancy.