Hereditary galactosemia

Abstract

Hereditary galactosemia is an inborn error of carbohydrate metabolism. Galactose is metabolized by Leloir pathway enzymes; galactokinase (GALK), galactose-1-phosphate uridylyltransferase (GALT) and UDP-galactose 4-epimerase (GALE). The defects in these enzymes cause galactosemia in an autosomal recessive manner. The severe GALT deficiency, or classic galactosemia, is life-threatening in the newborn period. The treatment for classic galactosemia is dietary restriction of lactose. Although implementation of lactose restricted diet is efficient in resolving the acute complications, it is not sufficient to prevent long-term complications affecting the brain and female gonads, the two main target organs of damage. Implementation of molecular genetics diagnostic tools and GALT enzyme assays are instrumental in distinguishing classic galactosemia from clinical and biochemical variant forms of GALT deficiency. Better understanding of mechanisms responsible for the phenotypic variation even within the same genotype is essential to provide appropriate counseling for families. Utilization of a lactose restricted diet is also recommended for GALK deficiency and some rare forms of GALE deficiency. Novel modes of therapies are being explored; they may be beneficial if access issues to the affected tissues are circumvented and optimum use of therapeutic window is achieved.

Early neurological complications in children with classical galactosemia and p.gln188arg mutation

“…Patients 16 years and older revealed delayed cognitive and social functions but showed normal fine and gross motor functions (Bosch et al, 2004). Speech disorders that cannot be explained by cognitive disabilities have been the most frequently reported abnormalities: they were found in 38–88% of patients, with a rate four‐to‐six‐fold higher than that of idiopathic childhood speech disorders (Potter et al, 2008, 2011; Coelho et al, 2017; Demirbas et al, 2018). Notably, speech disorder was present in 51.9% of a group of patients with a homozygous P.GLN188ARG mutation who had a higher median age than our group (Coss et al, 2013).…”

Atypical late presentation of galactosemia

“…2,3 Cataract in galactosemia is caused by lens galactitol accumulation, which induces hyperosmotic and oxidative stress. 4 Untreated infantile cataract affects normal visual development and leads to blindness, often requiring lensectomy. Once a galactose-free diet is instituted, there is typically prompt resolution of acute neonatal complications and cataracts can often be prevented and reversed.…”

“…Newborn screening for galactosemia is now available in many countries and is based on evaluation of GALT activity and (or) total galactose levels. 4 Screening allows early diagnosis and treatment, although some patients present clinically in the first few days of life before screening results are available, at times with life-threatening sepsis and liver failure.…”

Novel Neuropathological Features of a Child with an Epileptic Encephalopathy Due to Presumed Polyol Dysmetabolism

“…These include ribose-5-phosphate isomerase deficiency, enzymesassociated galactosemia, transaldolase deficiency, sorbitol dehydrogenase, L-arabitol dehydrogenase, and sedoheptulokinase. 1,[3][4][5][6][7][8] Defects in any of these enzymes are rare, with galactosemia being the most common and presents in infancy with lethargy, vomiting, diarrhea, and jaundice. 3 The others cause a variety of symptoms, most of which are due to accumulation of the polyol in tissue resulting in damage to liver, gastrointestinal, retina, and both peripheral and central nervous system (CNS).…”

“…The presence of elevated polyols has been most closely associated with diabetic peripheral neuropathy and retinopathy, 9,10 but has been less frequently associated with primary liver or neurological disorders including multiple sclerosis. 3,7,11 The mechanism of tissue changes related to polyols in diabetics has not been well elucidated. 9,10,12 A few studies have also described elevation of myo-inositol and other polyols in children with trisomy 21 13 and affective disorders.…”