Classic Galactosemia

Scenario 1 – Abnormal newborn screening (NBS) result and prompt initiation of appropriate management in the neonatal period

Within days of ingesting breast milk or lactose-containing formulas, infants with classic galactosemia develop life-threatening complications including feeding problems, failure to thrive, hypoglycemia, hepatocellular damage, bleeding diathesis, and jaundice (see Table 2).

If a lactose-free diet is provided during the first three to ten days of life, the signs of classic galactosemia resolve quickly and prognosis for prevention of liver failure, E coli sepsis, and neonatal death is good. Failure to implement effective newborn screening may have catastrophic consequences such as liver failure [Malone et al 2011].

Long-term outcome. Even with early and adequate therapy, the long-term outcome in older children and adults with classic galactosemia can include cataracts, speech defects, poor growth, poor intellectual function, neurologic deficits (predominantly extrapyramidal findings with ataxia), and, in females, hypergonadotropic hypogonadism or premature ovarian insufficiency (POI) [Rubio-Gozalbo et al 2019].

Classic galactosemia is associated with extreme variability in chronic complications and/or long-term outcome. Even individuals who have not been sick in the newborn period and who were begun on a lactose-free diet from birth (e.g., those with a prior affected sib in the family) may manifest language delay, speech defects, learning disabilities, cognitive impairment, and in females, POI. These problems may manifest as early as age one to two years, and in almost all instances, no findings that would have predicted eventual brain and ovarian dysfunction were present in early infancy. A minority of individuals may exhibit documented neurologic abnormalities including tremor (postural or intentional), cerebellar ataxia, and dystonia. No findings early in the disease course are good predictors of these long-term complications. Overall, the quality of life is reduced in adults with classic galactosemia, and more so when compared to individuals with phenylketonuria (PKU) [Gubbels et al 2011, ten Hoedt et al 2011, Hoffmann et al 2012].

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Scenario 2 – Symptomatic individual with untreated classic galactosemia (resulting from NBS not performed or false negative NBS result)

If classic galactosemia is not treated, sepsis with E coli, shock, and death may occur [Levy et al 1977]. Infants who survive the neonatal period and continue to ingest lactose may develop severe brain damage [Otaduy et al 2006].

If the diagnosis of classic galactosemia is not established, the infant who is partially treated with intravenous antibiotics and self-restricted lactose intake demonstrates relapsing and episodic jaundice and bleeding from altered hemostasis concomitant with the introduction of lactose. If treatment is delayed, complications such as growth restriction and progressive liver disease are likely. Rare affected individuals may develop vitreous hemorrhages that may produce blindness [Levy et al 1996, Takci et al 2012].

Long-term outcome. Information on long-term outcomes was initially reported by Waggoner et al [1990] as the result of a retrospective, cross-sectional survey of 270 individuals with classic galactosemia. The largest outcome study involving 507 people with classic galactosemia was published by the international GalNet registry or consortium [Rubio-Gozalbo et al 2019]. To summarize, the data on long-term outcome indicate that complications involving the nervous system and ovarian function do not correlate with any of the well-known biochemical variables (e.g., erythrocyte galactose-1-phosphate levels); furthermore, manifestations of one or more of these complications vary even among individuals with the same genotype associated with classic galactosemia (see Table 3) [Doyle et al 2010, Schadewaldt et al 2010, Hoffmann et al 2011, Krabbi et al 2011, Coss et al 2012, Waisbren et al 2012, Frederick et al 2017].

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Relationship between treatment and outcome. No significant associations were found between treatment and outcome except for a greater incidence of developmental delay among individuals who were not treated until after age two months. However, IQ scores were not highly correlated with the age at which treatment began. The effect of early treatment on outcome was also studied in 27 sibships, three of which had three affected sibs. The older sibs were diagnosed and treated after clinical symptoms occurred or newborn screening results had been reported, whereas the younger sibs were treated within two days of birth. Although the younger sibs were treated early and only one developed neonatal symptoms, the differences in IQ scores among the sibs were not statistically significant, and the speech and ovarian function of the younger sibs were no better than those of their older sibs.

Individuals with or without neurologic complications. No differences were observed in treatment or biochemical factors between the 56 individuals with normal intellect, speech, and motor function and the 25 individuals with developmental delay and speech and motor problems.

Relationships of complications. Developmental delay and low IQ scores were associated with speech problems, motor problems, and delayed growth, but not with abnormal ovarian function.

Sex differences. Females had lower mean IQ scores than males after age ten years (p<0.05) and had lower mean heights for age at five to 12 years (p<0.05), but did not differ in frequency of speech or motor problems or in the treatment variables, including age at which treatment began, neonatal illness, or galactose-1-phosphate erythrocyte concentration. However, the association of problems with intellectual development, speech, and motor function could also indicate a specific neurologic abnormality in some cases of galactosemia [Schadewaldt et al 2010].

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