Curious Neurologic Sequelae in Galactosemia

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Curious

Neurologic

Sequelae

in Galactosemia

Warren

Lo, MD, Seymour

Packman,

MD, Sylvia

Nash,

MD,

Kathleen

Schmidt,

RN, MS, Steven

Ireland,

MD,

Ivan Diamond,

MD, PhD,

Won

Ng, PhD,

and George

Donnell,

MD

Departments of Pediatrics and Neurology, University of California, San Francisco; Department of Pediatrics, Los Angeles Children’s Hospital and University of Southern California, Los Angeles

ABSTRACT. Two siblings with classic transferase defi-ciency galactosemia that was detected at birth have been

treated with lactose restriction since the neonatal period. Both patients developed a unique and progressive

neu-rologic syndrome of mental retardation, tremor, and

ataxia. Careful review of the family history and medical records, the absence of metabolic disturbances other than

those related to galactosemia, and the aggregate physical findings and neurodiagnostic studies ruled out other neu-rologic disorders in these siblings. It is therefore proposed that these patients represent a subgroup of transferase-deficient ga!actosemic patients, who develop

character-istic neurologic sequelae with conventional dietary

man-agement. The existence of this subgroup should be con-sidered in evaluations of therapeutic responses in cohorts

of patients with galactosemia. Further, galactosemia should be included in the differential diagnosis of tremor

and ataxia in the setting of mental retardation. Pediatrics 1984;73:309-312; galactosemia, galactose-1-phosphate

ur-idyl transferase, tremor, ataxia, mental retardation.

Classic transferase deficiency galactosemia is an autosomal recessive disorder with deficient activity

of ga!actose-1-phosphate uridyl transferase.’ The

institution of newborn screening programs has re-su!ted in early detection and prompt treatment by lactose restriction.25 The response to dietary inter-vention has been satisfactory in genera!, but not uniformly ,13-7 raising the possibility of biochem-ica! heterogeneity within the classic transferase deficiency group.

The presenting symptoms vary with age. Patients affected in the neonatal period often exhibit severe inanition, jaundice, hepatomegaly, and cataracts.

Received for publication Dec 14, 1982; accepted April 13, 1983. Reprint requests to (S.P.) Department of Pediatrics, Division of Genetics, University of California, San Francisco, San Fran-cisco, CA 94143.

American Academy of Pediatrics.

Patients with the syndrome detected later in life may evince only mental retardation or cataracts.1 Isolated case reports have noted unusual neuro!ogic findings that extend beyond the typical clinical spectrum. Huttenlocher and associates8 reported three infants with pseudomotor cerebri. Older pa-tients have been described with cerebellar ataxia, tremor, choreoathetosis, and an encephalopathy;

however, the etiology of the neurologic

abnorma!i-ties has in all instances been obscure and could not be clearly related to ga!actosemia.9’2

We report our studies of a brother and sister,

ages 19 and 16 respectively, with classic galactose-mia. Despite well-documented adequate dietary

management since birth, both siblings were

men-tally retarded, and both had tremor and prominent cerebellar signs. These findings are similar to din-ical abnormalities described in a few isolated case reports. The presence of identical neurologic ab-normalities in two siblings with galactosemia, and in other singleton cases, suggests that these neu-rologic features are associated with the disorder.

We propose that a triad of mental retardation,

tremor, and cerebellar dysfunction may be a char-acteristic neurologic syndrome that can develop in a subgroup of patients with transferase deficiency galactosemia.

CASE REPORTS

Case 1

J.P. was the 3.3-kg product of a normal pregnancy; he

was the son of 23-year-old unrelated parents. On day 8

of life, there began the gradual deveopment of lethargy,

vomiting, diarrhea, jaundice, and hepatomegaly. On day 13 of life, he was hospitalized and nonglucose mellituria

was detected. The symptoms resolved with a lactose

restriction which was instituted on day 17 of life and

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310 GALACTOSEMIA

While certain early milestones were appropriately

at-tamed (sitting, 6 months; walking, 1 year; words at 10

months), slow development was clearly evident by age 18

months, and speech acquisition proceeded quite poorly

from this point. Intelligence quotient was assessed as 56

at age 5 years. The most recent intellectual assessment

revealed a full-score IQ of 60.

Impaired coordination and tremor were first noted at age 5 years, and both progressed to the present age of 19

years. At age 5 years, he developed a trunca! ataxia which then progressed in severity until age 9 years, thereafter

remaining static. The patient was found to be generally

hypotonic at age 1 1 years, which remained unchanged up to the present evaluation. At the time of admission the

patient was too tremulous to drink from a cup. He could

walk independently, but was very unsteady.

Examination. The general physical examination of this

19-year-old white man was normal. The patient was

awake, alert, and oriented. His mood was labile, varying from jocularity to hostility. He spoke with dysarthria and

a tremulous voice. He had poor memory for recent and remote events. He was unable to read, recite the alphabet,

or calculate. His gait was awkward, with the patient

nearly incapable of tandem walking and balancing on one

leg. Cranial nerve examination was normal.

Ophtha!mo-logic examination was entirely normal. There was a

coarse resting tremor of the head and extremities which was increased with sustained posture and action. Muscle

tone was decreased in both upper extremities. Muscle bulk and strength were normal. Dysmetria with intention tremor was noted bilaterally on finger-to-nose-to-finger, and heel-to-knee-to-shin testing. Dysdiadochokinesis and a decreased check response were demonstrable in the upper extremities. Sensation was normal. Deep tendon reflexes were normal and the plantar responses were

flexor. Snout and bilateral grasp reflexes were present.

Case 2

D.P., the sister of patient 1 (J.P.), was born at term and had a birth weight of 3.2 kg. Because of the risk of carrying a galactosemic fetus, her mother consumed a lactose-free diet throughout pregnancy. D.P. was placed on lactose restriction at birth. Restriction was continued when the diagnosis of galactosemia was established, and

has been maintained through the present period. As with her brother, early milestones (sitting, walking)

were achieved at a normal age. Language development, however, was clearly delayed, and she did not talk until

after age 3 years. Her intellectual development was

sim-ilarly delayed, and at 12 years of age she had a mental

age of 5 years. Most recent assessment revealed a

full-score IQ of 65. Generalized hypotonia and a mild inten-tion tremor were detected at age 6#{189}years, and progressed gradually until age 16 years. The patient had not reached menarche by age 16 years.

Examination. The general physical examination at age 16 years was norma!. The patient was awake and alert. She could not follow complex commands. She spoke with a severe dysarthria, and could only use single words. Her

gait was awkward and she exhibited difficulty in tandem

walking. Cranial nerve examination was normal.

Ophthalmologic examination was entirely normal. There

was a coarse resting tremor of all extremities which

increased with movement and with sustained posture.

Muscle tone was generally diminished. Muscle bulk and

strength were norma!. Dysmetria and intention tremor

were present in the upper and lower extremities

bilat-erally. Sensation was normal. Deep tendon reflexes were

normal and the plantar responses were flexor.

RESULTS

In both patients the complete blood count; WBC

differential; ESR; urinalysis; thyroid function tests;

hepatic enzymes; and serum electrolytes, urea

ni-trogen, creatinine, and calcium were normal. In

J.P.,

the CSF

was obtained after a traumatic

punc-ture. RBC count was 1,300/FL, but the supernatant was clear, and the chemistries and opening pressure

were normal. The CSF of D.P. was normal. In

particular, CSF protein concentrations of both pa-tients were normal. Urine metabolic screening in

both children revealed no evidence of other meta-bo!ic diseases.

EEG, brainstem evoked responses, and visually

evoked responses were obtained in both patients.

In J.P., the electroencephalogram recorded low to

moderate voltage, with generalized 6 to 7 Hz 0

activity which increased with drowsiness. The rec-ord was felt to be a borderline normal EEG because of mild diffuse slowing. His brainstem evoked re-sponses were grossly abnormal irrespective of which

ear was stimulated, because of a poorly formed wave

IV/V complex that was poorly reproducibile. His

visually evoked responses were norma!.

In D.P., the EEG recorded predominant 6 to 7

Hz 0 activity with much #{244}slowing, both of which increased with light sleep. There was occasional predominance of slowing in the right occipital

re-gion. The EEG was felt to be abnormal with exces-sive generalized slowing and a possible slow wave

focus in the right occipital region. The brainstem evoked responses were grossly abnormal because of

poorly formed wave IV/V complex with stimulation of either ear. The visually evoked responses of D.P.

were normal.

The computed tomographic (CT) brain scan of

D.P.

demonstrated diminished roentgenographic attenuation of the white matter in the

periventric-ular regions. The CT brain scan of J.P. showed similar changes in the periventricular white matter, plus moderate ventricular enlargement. In neither

patient was there evidence of a structural cerebellar abnormality.

In D.P., who had not yet reached menarche,

follicle-stimulating hormone was 100 mIU/mL (n

=

4 to 20 mIU/mL) and luteinizing hormone was

67 mIU/mL (n = 5 to 25 mIU/mL). The laboratory

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TABLE 1. RBC Galactose-1-phosphate Uridyl Trans-ferase* Activity (% of Nor-mal) Starch Ge! Electrophoresis Mobility Presumed Genotype

J.P. 0 No fluorescence G-G

D.P. 0 No fluorescence G-G

* Measured according to published procedures.13’5

TABLE 2. Galactose Metabolites*

J.P. D.P.

RBC galactose-1-phosphate (mg/dL) 2.8 1.5

Plasma ga!actose (mg/dL) 1.0 1.0

Urine galactose (mg/dL) 2.5 1.0

Urine galactitol (mg/g of creatinine) 457 390

* Measured according to published procedures.”’5

data together with the delay in menarche were

consistent with hypergonadotropic hypogonadism.

Ga!actose-1-phosphate uridyl transferase assays (Table 1) were consistent with classic transferase deficiency homozygosity in J.P. and D.P., and het-erozygosity in their parents.’3’5

The patients’ diets were reviewed. Both were

treated with lactose restriction from the neonatal period, and during D.P.’s gestation the mother

con-sumed a lactose-restricted diet. Medical records

document the thorough training in such dietary control that was received by the parents, their receptivity to such information, and the avidity with which they paid attention to lactose intake. Since later childhood, the children have consumed a vegetarian diet with the only source of lactose

being trace amounts of milk solids in bread products (less than 1 g of lactose per day). On this regimen, the erythrocyte galactose-1-phosphate concentra-tions have been within the acceptable range for

treated galactosemic patients (Table 2).

DISCUSSION

Both patients have biochemical findings

consist-ent with classic transferase deficiency ga!actosemia,

and were treated with conventional postnatal and-in D.P.-prenata! dietary modifications. Both de-veloped a distinct set of neurologic findings not

usually associated with treated or untreated classic

galactosemia.

Isolated case reports have noted patients whose neurologic findings have been similar to those of our patients. Crome” described an 8 year old who developed severe jaundice in the first 2 weeks of life, and was found to have galactosemia after the

first month of life. He was treated thereafter, but

developed microcepha!y, severe mental retardation, and an “odd and stiff” gait. Autopsy findings were cerebellar degeneration, g!iotic white matter, and a

demye!ination of the globus pa!!idus similar to the type seen with kernicterus. Haberland et a!9

de-scribed the clinical and neuropathologic findings in

a 25-year-old man with classic galactosemia. The patient was not treated until 13 years of age, and he had suffered severe jaundice in infancy, recur-rent hypoglycemia, seizures, and status epilepticus

in childhood. He had severe mental retardation and choreoathetosis, but because of multiple complicat-ing conditions, his neuro!ogic findings could not, with certainty, be ascribed to galactosemia.

Iampol’skaia1#{176} described 15 patients with galacto-semia and neurologic findings. The individual cases were not described in detail; however, in most

pa-tients galactosemia had been untreated for at least the first year of life, and in some cases for more

than the first 3 years of life. Two patients were

described as spastic, hypertonic, rigid in a

“pa!li-dary” fashion with a mild tremor increased by vol-untary action. Five patients were described as hy-potonic, hyperreflexic, with a disconjugate gaze, and

limited in upward gaze. Jan and Wilson’2 described

a 19-year-old man who was treated with a lactose-free diet starting at 15 days of age. He was mildly retarded, and at 12 years of age developed a slowly progressive tremor. When examined at 19 years of age, he had scanning speech and a tremor of the voice, tongue, and soft palate. He was hypotonic and had a resting tremor of the extremities which increased with action.

In the above ga!actosemic patients, the neuro-logic findings were either noted in isolation, or were attributable to concomitant complicating

condi-tions. In contrast, our patients are brother and sister and they developed virtually identical pat-terns of language delay, mental retardation, tremor,

and ataxia in a setting of treated transferase defi-ciency galactosemia. There was no evidence for any other predisposing condition to account for their unique neurologic syndrome. A norma! family his-tory included a brother without either glactosemia or neurologic disease, and the absence in any other

family member of symptoms suggestive of

cerebe!-!ar degeneration or an hereditary tremor. Further, the aggregate data derived from physical

examina-tions and laboratory studies serve to exclude other

neuro!ogic disorders that could possibly present in

this fashion in childhood and early adulthood. Cer-tainly, the syndrome in our patients is especially

similar to that in the patient reported by Jan and Wilson,’2 and included components noted in other patients9’ above. We suggest, therefore, that this triad represents a neurologic syndrome which can

develop in glactosemia, and which represents a

distinct clinical variant of transferase deficiency

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312 GALACTOSEMIA

This study suggests that ga!actosemia should be considered in children who develop cerebe!!ar dis-ease and tremor in a setting of mental retardation. The presence of such neurologic findings in several isolated ga!actosemic patients and in the siblings described in the present report support the conten-tion that we are observing a distinct clinical variant of transferase deficiency ga!actosemia, and one that should be considered separately in clinical eva!ua-tions of cohorts of galactosemic children. The bio-chemical basis for the clinical heterogeneity re-quires further investigation.

Out patients’ neuro!ogic deficits cannot easily be explained by the direct or indirect toxic effects of

high ga!actose or ga!actose-1-phosphate concentra-tions. The brother was treated soon after presen-tation in the newborn period; the sister was on lactose restriction from birth. Both have been maintained on lactose restriction to the present day, with ga!actose-1-phosphate levels in an ad-ceptable range. Finally, it is notable that neither patient has ever developed cataracts.

Several investigators”35”8 have invoked pre-natal galactose toxicity as a contributing factor in the generation of mental retardation and other aspects of the ga!actosemia phenotype, including the hypergonadotropic hypogonadism observed in some females.’9 Such toxicity may, in fact, occur in the face of maternal prenatal lactose restriction.6’7 The precise etiology of the neurologic syndrome of

tlie ga!actosemia variant under discussion herein, and the relation of the syndrome to treatment, must

therefore be considered as part of the unresolved

and broader question of the etiology of toxicity

in treated and untreated galactosemia in gen-eral.37’17’9

ACKNOWLEDGMENTS

This work was supported by US Public Health

Service-National Institutes of Health grants No. GM28838 and

RR1271-01, and a grant from the March of Dimes-Birth Defects Foundation.

We thank Suzanne Wilson, MD, Doris Dare, RD,

Karen Knopf, MS, RD, and Judy Derstine, PHN, MS,

for assistance in the care and evaluation of these patients.

We thank Lydia Pennell for translation of papers from Russian to English. Further, we acknowledge the

contri-butions of Gary Goldstein, MD, and Bruce Berg, MD, in

the early phases of this work, and the editorial assistance

of Carol Dahlstrom and Beverly Cubbage in the

prepa-ration of this manuscript. Finally, these studies could not

have been performed without the cooperation of Elise

Doolittle.

REFERENCES

1. Donnel! GN, Bergren WR: The ga!actosemias, in Raine DN (ed): The Treatment oflnherited Metabolic Disease. London, Medical and Technical Publishing Co, Ltd, 1975, pp 91-114 2. Levy HL, Hammersen G: Newborn screening for

galactose-mia and other galactose metabo!ic defects. J Pediatr 1978;92:871

3. Donne!! GN, Collado M, Koch R: Growth and development of children with galactosemia. J Pediatr 1961;58:836 4. Komrower GM, Lee DH: Long-term follow-up of

galactose-mia. Arch Dis Child 1970;45:367

5. Donnell GN, Koch R, Bergren W: Observations on results ofmanagement of galactosemia patients, in Hsia DY-Y (ed): Galactosemia. Springfield, IL, Charles C Thomas, 1969 6. Komrower GM: Clouds over glactosemia. Lancet 1983;1:190 7. Clouds over galactosemia, editorial. Lancet 1982;2:1379 8. Huttenlocher PR, Hi!lman RE, Hsia YE: Pseudotumor

cer-ebri in galactosemia. J Pediatr 1970;76:902

9. Haberland C, Perou M, Brunngraber EG, et al: The neuro-pathology ofgalactosemia: A histopathologicaland biochem-ical study. J Neuropathol Exp Neurol 1971;30:431

10. Iampol’skaia El, Be!’mishchev YE, Ermakova LI, et al: Neurologic characteristics of glactosemia in children.

Pedia-tria 1978;11:37

11. Crome L: A case of galactosemia with the pathological and neuropatho!ogical findings. Arch Dis Child 1962;37:415 12. Jan JE, Wilson RA: Unusual !ate neurological seque!ae in

galactosemia. Dev Med Child Neurol 1973;15:72

13. Ng WG, Donnell GN, Bergren WR: Mannito! excretion in glactosemia patients. Clin Chim Acta 1975;64:39

14. Ng WG, Bergren WR, Donne!! GN: An improved procedure for the assay of hemolysate galactose-1-phosphate uridyl transferase activity by the use of ‘4C-labelled ga!actose-1-phosphate. Clin Chim Acta 1967;15:489

15. Ng WG, Bergren WR, Fields M, et a!: An improved electro-phoretic procedure for ga!actose-1-phosphate uridyl trans-ferase: Demonstration of multiple activity bands with a Duarte variant. Biochem Biophys Res Commun 1969;37:354 16. Chen YT, Mattison DR, Feigenbaum L, et al: Reduction in

oocyte number following prenatal exposure to diet high in galactose. Science 1981;214:1145

17. Chen YT, Mattison DR, Schu!man JD: Hypogonadism and

galactosemia. N Engl J Med 1981;305:464

18. Steinmann B, Gitze!man R, Zachmann M: Hypogonadism and galactosemia. N EngI J Med 1981;305:464

19. Kaufman FR, Kogut MD, Donnell GN, et a!:

Hypergo-nadotrophic hypogonadism in female patients with galacto-semia. N EngI J Med 1981;304:994

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1984;73;309

Pediatrics

Diamond, Won Ng and George Donnell

Warren Lo, Seymour Packman, Sylvia Nash, Kathleen Schmidt, Steven Ireland, Ivan