Hyperargininemia Presenting as Intermittent Ataxia and Cerebellar Atrophy.

Sir,

Hyperargininemia, one of the distal urea cycle defects (UCD), is due to complete or partial deficiency of the enzyme arginase – which is responsible for the lysis of arginine to ornithine and urea. It is one of the less frequent urea cycle disorders and is inherited in an autosomal recessive manner. Its incidence has been estimated between 1:350,000 and 1:1,000,000.[1] Hyperammonemic episodes occur neither commonly nor as severely as in other UCD. Symptoms usually noticed in childhood include developmental delay, progressive spastic diplegia, seizures and infrequently ataxia, athetosis, hyperactivity and hepatomegaly.[2] Salivary gland enlargement has so far been not reported in hyperargininemia. Here, we report a case of hyperargininemia who presented with intermittent ataxia, vomiting, bilateral parotid enlargement and cerebellar atrophy.

A 8-year-old female child, firstborn of third degree consanguineous parents, presented with frequent falls while walking due to crossing of legs since 4 years of age. The falls were more frequent in the last 6 months and hence the admission. No history of weakness of upper limbs or bladder involvement. No seizures either. Her milestones and scholastic performance were normal. Her younger sibling is normal. Examination revealed a conscious child with intact cranial nerves, bipyramidal signs in lower limbs and spastic gait. Fundi were normal. Her general examination was unremarkable except bilateral parotid enlargement.

MRI brain showed mild cerebellar atrophy [Figure 1]. Serum immunoglobulins, alpha feto protein, lipoproteins, vitamin B12, thyroid profile, lactate, pyruvate and ammonia were normal. In view of bilateral parotid enlargement, retroviral screening and vasculitic work up were done which were negative.

Figure 1

MRI brain T1 saggital view showing cerebellar atrophy

Meanwhile, she developed recurrent vomiting, truncal, gait ataxia, and could not stand or walk. Her ammonia level was high 2.88 μg/ml [0.15-0.60 μg/ml] with normal lactate and arterial blood gas analysis. Historical review revealed that she had two such episodes before. She was managed with intravenous dextrose and sodium benzoate in the dose of 250 mg/kg/day in divided doses. Vomiting and ataxia subsided over the next 2 days and serum ammonia levels came down to 1.1 μg/ml. Serum amino acids by HPLC showed high levels of arginine - 489 μM (10-140 μM). She was initiated on protein restricted diet and sodium benzoate continued. On follow-up, her ammonia levels are normal, parotid enlargement has subsided, gait has improved, is able to walk without falls, even able to dance. Her sibling had normal levels of arginine.

Arginase deficiency is one of the UCD caused by homozygous or compound heterozygous mutation of the arginase-1 gene (ARG1) on chromosome 6q23, which results in partial or complete deficiency of the enzyme arginase.

The clinical manifestations of arginase deficiency are strikingly different from other UCD such as progressive spastic diplegia, cognitive deficits, epilepsy, intermittent ataxia, hyperactivity and choreoathetosis.[3] Our child had spastic diplegia with intermittent ataxia. Hyperammonemic episodes are uncommon in hyperargininemia in contrast to other UCD, our child had three such episodes.

Clinical manifestations of arginase deficiency appear in childhood rather than in newborn period like other UCD is due to the fact that arginase exists in two isoforms - arginase I (ARG1) expressed in the liver, erythrocytes, salivary glands[4] and arginase II (ARG2) in the renal tissues. The milder presentation of ARG1 deficiency may be the result of over expression of ARG2. Moreover, mitochondrial arginase activity becomes up-regulated when the cytosolic arginase I activity in the liver is deficient.

Our patient had bilateral painless diffuse parotid enlargement for nearly a year and causes of bilateral parotid enlargement such as human immunodeficiency viral infection, rheumatological conditions were excluded. In patients with hyperargininemia, no enzyme activity was demonstrated in the saliva leading to high arginine levels in saliva, as arginase I is expressed in salivary glands also. The elevated arginine could augment nitric oxide synthesis and leads to oxidative damage in the organs.[5] We speculate that the oxidative stress associated with hyperargininemia leads to increased susceptibility of salivary glands to oxidative damage causing enlargement. Salivary gland enlargement in arginase deficiency has not been reported hitherto.

MRI brain findings are usually non-specific such as cerebral atrophy.[6] Carvalho et al. have reported normal MRI brain in most of their patients, a variable degree of cerebral atrophy in others and cerebellar atrophy in 3 patients.[7] Our child had cerebellar atrophy which is rare.

Three- to fourfold elevation of plasma arginine is highly suggestive of arginase deficiency. Diagnosis can be confirmed by molecular genetic testing or low enzyme activity in red blood cell extracts.[8] Our child had more than threefold elevation of plasma arginine. Molecular genetic studies could not be done for want of facilities.

Acute management includes stopping protein intake, providing calories by intravenous dextrose with or without insulin to prevent catabolism, nitrogen scavengers such as sodium benzoate or sodium phenyl butyrate. If ammonia levels are high > 250 micromoles/L, hemodialysis is recommended. Long term management includes protein restricted diet, ammonia detoxifiers and prompt treatment of intercurrent infections.

With adherence to a dietary and drug regimen, a favorable outcome can be expected, with cessation of further neurological deterioration and in some instances, of improvement. Orthotic liver transplantation is a treatment option when conventional treatment fails.[9] Evaluation of relatives at risk especially the younger siblings is important so that morbidity can be reduced by early management in those who are affected.

In conclusion, hyperargininemia should be considered as one of the differentials for intermittent ataxia in children. Early and prompt treatment would improve the outcome.

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Conflicts of interest

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