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Classical galactosemia revisited
Bosch, A.M.
Publication date 2004
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Citation for published version (APA): Bosch, A. M. (2004). Classical galactosemia revisited.
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Download date:26 Sep 2021 6 6 Classicall galactosemia versus galactokinase deficiency,, a comparative study with implications forr a potential therapy
Partt of this chapter has been published as: Clinical features of galactokinasee deficiency: a review of the literature JJ Inherit Metab Dis 2002; 25:629-34
A.M.. Bosch1-3 H.D.. Bakker1 A.H.. v Gennip2 J.V.. v Kempen4 R.J.A.. Wanders1-2 F.A.. Wijburg1
Fromm the department of Pediatrics and the laboratory Genetic Metabolicc Diseases, Academic Medical Centre, University of Amsterdam;; department of Pediatrics, Gooi-Noord Hospital, Blaricum;; 4Dutch Society for Galactosemia, The Netherlands. Abstract t
Galactokinasee deficiency (McKusick 230200) is a rare autosomal recessive inborn error of galactosee metabolism. Cataract and, rarely, pseudotumour cerebri caused by galactitol accumulationn seem to be the only consistently reported abnormalities in this disorder (Holton ett al 2001). We performed a literature search to obtain information on the clinical spectrum off galactokinase deficiency. A total number of 25 publications were traced describing 55 galactokinasee deficient patients. Cataract was reported in most patients. Clinical abnormalities otherr than cataract were reported in 1 5 (35%) out of 43 cases on which information was available.. However, all symptoms were reported infrequently and a causal relationship with thee galactokinase deficiency is unlikely. As indeed cataract and pseudotumor cerebri appearr to be the sole complications of galactokinase deficiency, outcome for patients with galactokinasee deficiency is much better than for patients with classical galactosemia (McKusickk 230400), a more common autosomal recessive disorder of galactose metabolism causedd by galactose-1-phosphate uridyltransferase (GALT;EC 2.7.712) deficiency. Long term follow-upp of patients with this disorder has shown that, in spite of a severe galactose restrictedd diet, most patients develop abnormalities such as a disturbed mental and/or motorr development, dyspraxia and hypergonadotrophic hypogonadism. Endogenous productionn of galactose has been considered an important etiological factor. Althoughh part of the damage in classical galactosemia may already occur in utero, available evidencee suggests that damage will continue after birth. Inhibition of galactokinase may thuss be a promising approach to control damage in GALT deficient patients.
92 2 Classicall galactosemia versus galactokinase deficiency
Introduction n
Galactokinasee deficiency (McKusick 230200) is a rare autosomal recessive inborn error of
galactosee metabolism. In the Leloir pathway, galactokinase (EC 2.7.1.6) catalyses the
phosphorylationn of galactose with ATP to galactose-1-phosphate. The disorder was first
describedd by Gitzelmann (1965, 1967). The estimated incidence varies. Thalhammer et al
(1968)) reported the first case discovered in a newborn screening program after screening
35.7700 neonates for hypergalactosemia. Mayes and Guthrie (1968) determined galactokinase
activityy in a mostly Caucasian population and reported an estimated incidence of
heterozygotess of 1:107. They concluded that galactokinase deficiency should occur in about
1:: 40,000 to 1: 50,000 births. Levy (1980) however found only six neonates with
galactokinasee deficiency after screening 6,000,000 infants for hypergalactosemia. As a
numberr of the reported patients were of gypsy ancestry, the incidence may vary among
differentt populations (Gitzelmann 1965; Kalaydjieva et al 1999; Linneweh et al 1970;
Thalhammerr et al 1968). Stambolian and colleagues (1995) localized the human
galactokinasee gene, GK1, to the 17q24 region and many private mutations have been
reportedd in galactokinase deficient patients (Hunter et al 2001; Kolosha et al 2000;
Stamboliann et al 1995). In Roma patients a founder mutation (P28T) was reported
(Kalaydjievaa et al 1999).
Cataractt caused by galactitol accumulation seems to be the only consistent abnormality in
galactokinasee deficiency (Holton et al 2001) and this can be prevented with a galactose
restrictedd diet. However, other abnormalities have been reported in association with
galactokinasee deficiency, but it is unclear whether these are a result of galactokinase enzyme
deficiencyy (Segal et al 1979).
Thiss relatively benign course of the disease is in strong contrast with the high percentage of
latee complications such as problems of mental development, verbal dyspraxia and delayed
vocabulary,, deficits of cognitive function, disorders of motor function, and
hypergonadotrophicc hypogonadism that have been reported in classical galactosemia
(Schweitzerr 1993; Waggoner 1990). Nevertheless, since most patients with galactokinase
deficiencyy have been reported as isolated patients it is difficult to obtain a good overview of
thee pathology. In view of potential therapies for classical galactosemia, aimed at inhibition
off galactokinase, we performed a literature search to obtain information on the clinical
spectrumm of galactokinase deficiency in comparison with classical galactosemia.
Chapterr 6 93 3 Method d
AA search was done in EBSCO Medline and PubMed with the terms galactokinase deficiency // human. We searched for publications in English, German, French and Dutch. Only 71 publicationss were retrieved. The abstracts were screened for patient reports. References in Holtonn and colleagues {2001) were checked and publications not previously found in EBSCO Medlinee or PubMed were added. Of all retrieved publications containing clinical information, referencess were carefully checked for additional clinical reports.
94 4 Classicall galactosemia versus galactokinase deficiency
Results s
AA total number of 25 publications were traced, describing 55 galactokinase deficient patients.
Inn all cases the diagnosis was established by demonstrating the deficient activity of the
galactokinasee enzyme, usually in erythrocytes. Publications reporting galactokinase variants
weree excluded. Some patients have been described in more than one publication. Only the
publicationn containing the most clinical information on each patient is included.
(Beutierr et al 1973; Borzy et al 1984; Colin et al 1976; Cook et al 1971; Dahlqvist et al
1970;; Gitzelmann 1965, 1967; Kaloud et al 1972; Kalaydjieva et al 1999; Kerr et al 1971;
Koloshaa et al 2000; Kurt et al 2002; Levy et al 1972; Linneweh et al 1970; Litmann et al
1975;; Monteleone et al 1971; Olambiwonnu et al 1974; Pickering and Howel 1972; Segal
etall 1979; Sitzmann et al 1977; Stambolian etal 1995; Thalhammer et al 1968; Vecchio et
all 1976; Vigneron etal 1970; Xu etal 1989).
Thee combined results are shown in Table 1. Cataract is a frequent feature in the galactokinase-
deficientt patients. Only patients detected by neonatal screening did not suffer from cataract.
Clinicall abnormalities other than cataract were reported in 15 (35%) out of 43 cases on
whichh information was available. Central nervous system abnormalities (mental retardation,
neurofibromatosis,, neurological deterioration, epilepsy and pseudotumor cerebri) were
reportedd in 8 (19 %) out of 43 cases. Mental retardation was described in 3 (7%) out of 43
Tablee 1. Family history and Symptoms in galactokinase deficiency
Featuree number of cases with feature/ % numberr of informative cases consanguinityy 9/35 26 gypsyy ancestry 11/27 40 cataractt 24/32 75 mentall retardation 3/43 7 epilepsyy 1/43 2 neurologicall deterioration 1/43 2 neurofibromatosiss 1/43 2 pseudotumorr cerebri 2/43 5 asphyxiaa 1/43 2 prematuree birth 1/43 2 smalll for gestational age 3/43 7 failuree to thrive 1/43 2 sloww feeding 1/43 2 hypoglycemiaa 1/43 2 hepatosplenomegalyy 2/43 5 C22 complement deficiency 1/43 2
Chapterr 6 95 5 patients.. Two of them are brothers with cataract, mental retardation and severe speech delay,, reported by Segal (1979). One patient with mild mental retardation was reported by
Koloshaa and colleagues (2000). Gitzelmann (1965, 1967; Gitzelmann et al 1974) reported thee first galactokinase deficient patient, a male with galactokinase deficiency and neurofibromatosis.. His mother also suffered from neurofibromatosis. His intelligence was normall and his neurological complications were consistent with the neurofibromatosis.
Pickeringg and Howel (1972) described a girl with neurological deterioration after developing severee epilepsy from age 17. She was diagnosed with cataract at age 4 and was treated withh a diet for a possible GALT deficiency. This girl was later found to have galactokinase deficiency.. In two patients with normal psychomotor development aspecific EEG abnormalitiess were reported (Dahlqvist et al 1970; Kaloud et al 1972). Pseudotumor cerebrii was described as a presenting feature in two patients. Both recovered after starting thee diet and developed normally (Colin et al 1976; Litmann et al 1975)
Prematurityy and neonatal asphyxia were mentioned once (Kerr et al 1971; Pickering and
Howell 1972). Three children (7 %) were small for gestational age, one suffered from failure too thrive (Kolosha et al 2000; Linneweh et al 1970; Pickering and Howel 1972). A transient mildd hepatosplenomegaly with normal liver enzymes was reported in 2 children at the time off diagnosis (Kerr et al 1971; Thalhammer et al 1968). Poor feeding which improved after thee start of the galactose restricted diet was reported in one patient (Dahlqvist et al 1970).
Anotherr patient had a single episode of hypoglycemia (1.8 mmol/L) at the time of diagnosis att 8 weeks of age (Cook et al 1971).
AA deficiency of C2 complement was reported in one patient. However, she had a sibling withh normal galactokinase activity who also suffered from C2 deficiency. In this patient growthh was reported to be below the 5th percentile (Borzy et al 1984). Finally, one remarkable
patientt was reported with galactokinase deficiency in the neonatal period but increasing galactokinasee activity with time and normalisation after 7 months (Vigneron et al 1970). Classicall galactosemia versus galactokinase deficiency
Discussion n
Otherr than cataract, no consistent abnormalities were reported in galactokinase deficient
patients.. The reported association of neurofibromatosis and C2 deficiency is unlikely to be
relatedd to the galactokinase deficiency in these patients. Pseudotumor cerebri has been
reportedd in two patients with galactokinase deficiency (Colin et al 1976; Litmann et al
1975)) as well as in three patients probably suffering from classic galactosemia (presenting
withh galactosuria, jaundice, feeding problems, liver function abnormalities and red blood
cellss unable to convert galactose to C02) (Huttenlocher et aM 970), and resolved completely
afterr starting the diet. The common pathogenic factor in both disorders is the accumulation
off galactitol, resulting in osmotic swelling, which is associated with both cataract and
pseudotumorr cerebri (Wang et al 2001).
Thee relationship between the galactokinase deficiency and the mental retardation that was
reportedd in 3 patients is unclear. As the 21 year old girl (Pickering and Howel 1972) had
beenn on a galactose restricted diet since 4 years of age, the galactokinase deficiency does
seemm an unlikely cause for her neurological deterioration and severe epilepsy at the age of
177 years. The mental retardation described in the two brothers by Segal and colleagues
(1979)) is unlikely to be related to the deficiency of galactokinase. Details of the mild
retardationn as reported by Kolosha and colleagues (2000) in a patient are not given in their
paper.. To our knowledge, psychomotor retardation has only been described in these three
discussedd cases and not in any of the other patients. All other symptoms were reported
infrequentlyy and a causal relationship with the galactokinase deficiency is highly unlikely.
Ass indeed cataract and, rarely, pseudotumor cerebri appear to be the sole complications of
galactokinasee deficiency, the outcome for patients with galactokinase deficiency seems to
bee much better than for patients with classical galactosemia. The pathogenic factors in
classicall galactosemia are not known. In the GALT deficient mice created by Ning and
colleaguess (2000), galactose-1 -phosphate was found to accumulate in liver, kidney and
brainn with very high levels of galactose-1-phosphate in red blood cells, comparable to the
findingss in GALT deficient humans. Surprisingly, these mice showed no evidence of galactose
toxicity.. However, the concentrations of galactitol in these GALT deficient mice were
significantlyy lower than observed in humans. This is probably caused by the low levels of
aldosee reductase in normal mouse tissues (Ai et al, 2000). Possibly it takes the combination
Chapterr 6 97 7 off both high levels of galactitol and high levels of galactose-1-phosphate to cause the pathologicc abnormalities found in classical galactosemia.
Therefore,, prevention of the formation of galactose-1 -phosphate by inhibiting galactokinase activityy or the formation of galactitol by inhibiting aldose reductase activity (Segal 2004) by usingg selective inhibitors might be a new therapeutic approach in preventing complications inn patients with GALT deficiency. Strategies like this have been reported to be successful in otherr metabolic diseases. In Gaucher disease (Cox et al 2000), lowering the rate of biosynthesiss of glucocerebroside by OGT 918 improves key clinical features of the disease.
Lindstedtt and colleagues (1992) reported successful treatment of hereditary tyrosinaemia typee I by inhibiting 4-hydroxyphenyl-pyruvate dioxygenase with NTBC and thus preventing thee accumulation of precursors and their toxic derivates of the substrate of the defective enzyme.. A crucial point in considering this approach for classic galactosemia is whether the damagee occurs in utero or later in life. Pathways of galactose metabolism develop around thee tenth week of gestation and abnormal levels of metabolites were found in fetuses from thee age of 20 weeks (Holton 2001). Cataractous changes were found by electron microscopy inn both eyes of a 5 months old fetus with classic galactosemia (Vannas et al 1975). However, mostt newborns develop cataract only after exposure to galactose from the diet. Also ovarian failuree seems to develop later in life: one patient had normal ovaries at the age of 7 and streakk gonads at 17 years and a second patient developed ovarian failure only some time afterr giving birth to a child (Kaufman et al 1981). A third patient who died with E Coli sepsis hass been reported with normal ovaries at the age of five days (Levy 1984). A decrease of
IQQ with increasing age has been reported in some reports (Schweitzer et al 1993, Waggoner ett al 1990). However, to our knowledge no individual longitudinal testing has been reported inn the literature. Although damage may well occur in utero, available evidence suggests thatt damage will continue after birth. Inhibition of galactokinase and/or aldose reductase mayy thus be a promising approach to control damage in GALT deficient patients. To this endd we are now developing selective inhibitors of galactokinase. Classicall galactosemia versus galactokinase deficiency
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100 0 Classicall galactosemia versus galactokinase deficiency
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Chapterr 6 101 1 —I I