Riboflavin-responsive glutaric aciduria type II presenting as a leukodystrophy

ELSEVIER

Rib o fl a v i n - R e s p o n s i v e G l u t a r i c

A c i d u r i a

Type II Presenti n o a

as

n - e u - o o- y s 'tr o p - y

Graziella Uziel, MD*, Barbara Garavaglia, MS*, Elisa Ciceri, MD*, Isabella Moroni, MD*, and Marco Rimoldi, MS*

hypoketotichypoglycemiaand lipid storage myopathy [1]. Acute metabolic episodes of hepatic failure and muscular wasting may be so severe as to cause coma or respiratory failure leading to severe brain damage or death. Three different biochemical conditions may be responsible for this disorder: electron transfer flavoprotein (ETF)deftciency, electron transfer flavoprotein coenzyme Q reductase (ETF:QO)deficiency [2], and a form of uncertain etiology, described for the first time by Gregersen et al. [3], which is responsive to riboflavin supplementation. We present a patient and his brother, who both have riboflavin-responsive GA II with a peculiar phenotype characterized by progressive central nervous system (CNS) dysfunction.

Case Report The clinical phenotype of multiple acyl-CoA dehydrogenase deficiency in infancy is characterized by r e c u r r e n t episodes of hypoketotic hypoglycemia and lipid storage myopathy. Brain damage has been described only a s a consequence of severe and protracted hypo-

glycemia. We describe a child who experienced normal physical and psychomotor development until the age of 3 years, who then developed progressive intention tremors, dysarthria, ataxia, and spastic tetraparesis, Episodes of acute metabolic distress w e r e n e v e r observed. Magnetic resonance imaging disclosed abhormal signals within the white matter of the brain and cerebellum, suggesting leukodystrophy. Gas chromatography/mass spectrometry analysis revealed abnormary high levels of glutaric acid, dicarboxylic acids, and glycine derivatives in urine. Riboflavin therapy

was initiated at 4 years of age, when the patient had already lost control of trunk and head posture. Consistent improvement rapidly occurred after riboflavin supplementation. Giutaric aciduria type II may cause brain damage, in spite of the absence of acute metabolic distress, and should be considered in the differential diagnosis of leukodystrophies. Uziel G, Garavaglia B, Ciceri E, Moroni I, Rimoldi M. Riboflavin-responsive glutaric aciduria type II presenting as a leukodystrophy. Pediatr Neurol 1995;13:333-335.

Introduction The clinical phenotype of glutaric aciduria type 1I (GA II) in infancy is characterized by recurrent episodes of

From the Departments of *Child Neurology; *Biochemistry and Genetics; and *Neuroradiology; Istituto Neurologico C. Besta; Milan, Italy.

© 1995 by Elsevier Science Inc. • 0887-8994/95/$9.50 SSDI 0887-8994(95)00187-5

The patient, a boy, was the first child of healthy, nonconsanguineous parents. Pregnancy, birth, and neonatal period were normal. Body weight at birth was 3,500 gm. Physical and psychomotor development were normal until 3 years of age, when tremor of the upper limbs ensued, followed by paraparetic ataxic gait and slurred speech. Signs of CNS dysfunction rapidly progressed and after 6 months he had lost the ability to walk alone and to speak. At 4 years, he was admitted to our institution. Physical examination disclosed a normally developed child with severe ataxia, spastic paraparesis, very brisk deep tendon reflexes, Babinski sign, and tremors of the upper limbs. He was unable to stand or sit without support; head control was poor. Although unable to speak because of anarthria, he was alert and understood spoken language. Electrophysiologic examination disclosed a slow, irregular, dysrhythmic EEG, normal visual and auditory evoked potentials, and normal electromyogram with normal motor and sensory conduction velocities. Magnetic resonance imaging disclosed leukodystrophic changes consisting of bilaterally and symmetrically increased signal intensity in the proton density T2-weighted images in the cerebral and, to a lesser extent, in the cerebellar white matter (Fig I A,B). T~-weighted images demonstrated a less evident hyperintense signal with the same distribution. The following laboratory findings were normal: erytbrocyte, leukocyte, and platelet counts, serum electrolytes, glucose, creatinine, urea, "y-glutamic transaminase, adenosine phosphatase, creatine phosphate, ammonia and coagulation parameters. Serum transaminases were elfrated: glutamic-oxaloacetic transaminase 330 U/L (normal range: 0-40 U/L), glutamic pyruvic transaminase 354 U/L (normal range: 0-40 U/L). At admission, metabolic acidosis was present (pH: 7.34, Pco2:33 mm Hg, P%: 73 mm Hg, H c o ~ - : 16, BE: - 6 ) with moderated increase of plasma lactate level: 2.3 btmol/L (normal range: 0.5-1.8 i.tmol/L). Biochemical investigations excluded metachromatic leukodystrophy, Krabbe disease, Canavan disease, and adrenoleukodystrophy. Free plasma camitine was reduced to 16.5 p.mol/L (normal range: 22-50 ~mol/L), but long chain acylcamitines were markedly increased at 9.2 ~zmol/L (normal range: 0.6-2.0 txmol/L). The 24-hour urinary excretion of organic acids had a pattern corresponding to GA II (Table I). Therapy with riboflavin 50 mg/day was initiated. After 6 months of riboflavin supplementation there was progressive improvement of the

Communications should be addressed to: Dr. Uziel; Istituto Neurologico C. Besta; Via Celoria, I 1; 20133 Milan, Italy. Received May 9, 1995; accepted August 23, 1995.

Uziel et al: Riboflavin-Responsive GA II

333

A

B

C

Figure 1. Cerebral MRI of Patient 1 (0.5 T, T2-weighted images; TR:2,100 ms, TE:IO0 ms). Axial section (A) displays high signal intensity in bilateral supratentorial white matter and subcortical regions with partial involvement of U-fibers; signal abnormalities are visible in the splenium and corpus callosum. Coronal section (B) displays the involvement of cerebellar white matter. (C) Images obtained after 18 months of therapy. neurologic condition: gait ataxia was still evident, but the patient was able to walk with minimal support and the upper limb tremors had disappeared; however, mild dysarthria and brisk tendon reflexes were still present. Neurologic examinations were performed every 4 months: improvement progressed steadily, resulting in full recovery after 1 year of therapy. The patient, now 6 years old, is free of symptoms and his motor and mental performances are normal. In spite of the normalization of the neurologic conditions, magnetic resonance imaging performed after 18 months of therapy did not disclose significant changes of the signal abnormalities, although the bulk of the white matter was slightly reduced (Fig 1C). The only brother of the propositus was a 3-year-old child who presented severe psychomotor developmental delay. He experienced fiequent epileptic seizures from the age of 6 months. During one of these episodes, he manifested prolonged asphyxia, associated with severe hypoglycemia, resulting in permanent brain damage. No further investigations were performed at that time. Physical examination disclosed profound hypotonia, increased tendon reflexes, poor posture control, and severe mental impairment. Levels of plasma carnitine and acylcarnitine esters were similar to those found in the brother (free carnitine: 7.1 Ixmol/L, long chain acylcarnitine esters: 7.0 ixmol/L). Urinary organic Table 1.

Urinary organic acids in patients with GA II

Controls

Pre

Patient

Post

Pre

Sibling

Post

Lactate Pyruvic acid

568 77

80

78

24

29