A Tale of Treatable Infantile Neuroregression and Diagnostic Dilemma with Glutaric Aciduria Type I.

Nutritional deficiencies related neurological manifestations are not uncommon in infants and children. Here, we describe an infant with Vitamin B12 deficiency due to depleted maternal Vitamin B12 status presenting with progressive encephalopathy and extrapyramidal signs. Diagnosis of infantile tremor syndrome was established in our patient based on the clinical and biochemical parameters. Magnetic resonance imaging had shown frontotemporal atrophy with widened Sylvian fissures and prominent cerebrospinal fluid spaces. Clinical and imaging findings might create a diagnostic dilemma with glutaric aciduria type I. Knowledge and identification of infantile tremor syndrome are essential, as it is a potentially treatable disorder. Our patient had significant developmental gains with Vitamin B12 treatment and infant stimulation program. Vitamin B12 deficiency must be looked for as a cause of neuroregression in children hailing from low socioeconomic status, infants of vegetarian mother, and infants with delayed or improper weaning. Screening for Vitamin B12 deficiency is essential in all infants and children with unexplained neuroregression, as this disorder is potentially treatable. More population-based studies in India are needed to explore the prevalence of Vitamin B12 deficiency in pregnant and lactating women and also to assess the need for Vitamin B12 supplementation during pregnancy and lactation.

INTRODUCTION

Various causes of infantile encephalopathies are biotinidase deficiency, glutaric aciduria (GA), neuronal ceroid lipofuscinosis, Alpers disease, Krabbe disease, metachromatic leukodystrophy, Niemann–Pick disease, GM1 gangliosidosis, GM2 gangliosidosis, Menkes disease, Alexander disease, Canavan disease, and congenital disorders of glycosylation. Here, we describe an infant with Vitamin B12 deficiency due to depleted maternal Vitamin B12 status presenting with progressive encephalopathy and extrapyramidal signs. Magnetic resonance imaging (MRI) had shown frontotemporal atrophy with widened Sylvian fissures and cerebrospinal fluid (CSF) spaces creating a diagnostic dilemma with GA type I (GA-I). Knowledge and identification of infantile tremor syndrome are essential, as it is a potentially treatable disorder.

CASE REPORT

A 6-month-old infant born fourth in birth order to a nonconsanguineously married couple from a lower socioeconomic background was brought for the evaluation of insidious onset gradual regression of all milestones noticed since 4 months of age. Mother’s antenatal period was unsupervised, and she had not received iron or folate supplementation. The infant was born full term by normal vaginal delivery at home, and infant had cried immediately after birth. Birth weight was not documented. At 4th month of age, he had complete head control, social smile, midline hand regard, and good eye contact with visual following of toys, and he could also localize the sound source.

Parents have noticed hyperpigmentation spots over the dorsum of the hand and feet from the 2nd month of age. From the 4th month of age, he had insidious onset gradual loss of all milestones. He had excessive irritability, poor eye contact, and loss of social interaction. He had bleating cry and floppiness of limbs. Coarse tremors involving both hands that disappeared during sleep were also observed. There was no history of myoclonus or seizures. He was on exclusive breast feeds, and mother was a strict vegetarian. There was no history of recurrent loose stools or diarrhea.

Anthropometry assessment had revealed a head circumference of 40 cm (<3rd centile), weight of 7060 g (3rd–50th centile), and length of 62 cm (<3rd centile). Sparse hypopigmented hair, and hyperpigmented spots over the dorsum of both hands and feet were detected on general physical examination [Figure 1a–c]. Anemia was also observed. He had no eye contact or social smile. Axial and appendicular hypotonia were observed. There were coarse tremors involving both hands. Muscle stretch reflexes were exaggerated. Bilateral plantar responses were extensor.

Figure 1

Clinical photograph of child with infantile tremor syndrome. (a) shows sparse, hypopigmented hair (b) shows hyperpigmentation over the dorsum of foot and nail beds (c) shows hyperpigmentation over the dorsum of hand and knuckles

Baseline laboratory findings are summarized in Table 1. Peripheral smear study had shown macrocytosis. Blood-borne virus screening was negative. Testing for antiparietal cell and anti-intrinsic factor antibodies was negative. Serum iron, ferritin, iron binding capacity, and magnesium levels were normal. Serum copper was 64 μg/dL (70-170 μg/dL), and ceruloplasmin was 581 U/L (200-1100 U/L). Serum methionine level was below detection range. However, urine homocysteine excretion was not elevated. Urinary organic acid analysis by gas chromatography/mass spectrometry had shown elevation of methylmalonic acid. Serum biotinidase assay was normal. Magnetic resonance imaging (MRI) brain [Figure 2a] had shown frontotemporal atrophy with widened Sylvian fissures and prominent CSF spaces. Myelination and deep grey nuclei were normal. Similar pattern of frontotemporal atrophy, prominent CSF and widened Sylvian fissures are seen in a child with glutaric aciduria type I [Figure 2b]. Involvement of deep grey nuclei is the key differentiating radiological feature between an infant with infantile tremor syndrome and glutaric aciduria type I [Figure 2b].

Table 1

Laboratory findings in child with infantile tremor syndrome before and after treatment

Figure 2

Magnetic resonance imaging brain (a) T2 axial images of our patient with infantile tremor syndrome show frontotemporal atrophy with prominent cerebrospinal fluid spaces (white arrow) and widened Sylvian fissures (black arrows). (b) T2 axial images of a child with glutaric aciduria type I show similar features of diffuse cerebral volume loss, predominantly involving frontotemporal region along with widened Sylvian fissures (bold black arrows) and subdural effusion (white arrow). There is symmetrical hyperintensity of bilateral caudate (double black arrows) and putamen (thin black arrow)

His mother’s hemoglobin was 11.8 g/dL, total leukocyte count was 4000 cells/cumm, platelet count was 231,000 cells/cumm, and mean corpuscular volume was 105.9 fL. Her blood homocysteine and Vitamin B12 were 39.23 μmol/L and 96 pg/mL, respectively. Diagnosis of infantile tremor syndrome was arrived based on subacute regression of milestones, coarse tremor, hyperpigmentation of skin over dorsum of hands and feet, low Vitamin B12, elevated urinary methylmalonic acid and elevated homocysteine. In an infant with GA-I, the onset is usually acute with encephalopathy, regression of milestones, extrapyramidal involvement, and macrocephaly. This disorder can be diagnosed by the detection of elevated blood glutaryl carnitine by tandem mass spectrometry and increased urinary excretion of glutaric acid and 3-OH-glutaric acid detected by gas chromatography/mass spectrometry. Mutation analysis of glutaryl CoA dehydrogenase (GCDH) gene helps in confirming the diagnosis. Our patient was initiated on Vitamin B12 500 μg administered intramuscular once daily for 14 days followed by once a month maintenance dose. Mother was also initiated on intramuscular Vitamin B12 therapy. The child was also supplemented with Vitamin D, calcium, and multivitamins, and he was also initiated on infant stimulation program.

After 4 months of treatment, he was able to sit without support and produce cooing sounds. He had poor eye contact, auditory agnosia, and excessive finger play. Vision and hearing were normal. There was a complete disappearance of hyperpigmented macules and tremor. Tone and power assessment were normal. Blood parameters and Vitamin B12 level after treatment are summarized in Table 1. With intensive stimulation therapy and continued Vitamin B12 supplementation, child was observed to have significant developmental gains during second follow-up assessment after 6 months.

DISCUSSION

Vitamin B12 is essential for normal growth and development in fetus, infants and children. B12 cofactor is a complex organic cofactor and B12 dependent enzymes are involved in complex metabolic pathways.[1] Deficiency of Vitamin B12 causes hematological, mucocutaneous, neurological, psychiatric, and gastrointestinal manifestations. The first report of Vitamin B12 deficiency associated neurodegeneration in infants was described by Jadhav et al.[2] Inadequate intake of animal products, infants of vegetarian mother, defects in absorption and processing of cobalamin are the clinical settings with high risk for Vitamin B12 deficiency.[3] In our case, low Vitamin B12 level had resulted from depleted maternal serum Vitamin B12 status. Vitamin B12 in breast milk correlates with maternal B12 status.[4]

Delayed myelination, dysmyelination, impaired s-adenosylmethionine synthesis, increased odd-chain fatty acid synthesis, increased tumor necrosis factor-α, increased epidermal growth factor, and impaired aerobic metabolism observed with Vitamin B12 deficiency could explain the impact on neurodevelopment.[4] Although age at onset, neuroregression, and extrapyramidal symptoms raised the suspect for GA-I in our case, the pointers such as subacute onset of symptoms, bleating cry, hypopigmented scalp hair, knuckle, and diffuse skin hyperpigmentation, and absence of large head guided us in establishing the diagnosis of infantile tremor syndrome. Furthermore, our patient was an infant of vegetarian mother, thereby predisposing to Vitamin B12 deficiency. Pancytopenia was documented in our case as reported previously in the literature.[56]

MRI findings described in patients with Vitamin B12 deficiency were delayed myelination, signal changes in periventricular white matter, centrum semiovale, internal capsule, middle cerebellar peduncle, frontal cortex (Morel’s laminar necrosis), corpus callosum, and anterior, lateral, and posterior columns of spinal cord.[789101112] Ventricle dilatation, cortical atrophy, thinning of corpus callosum, subdural effusion, and external hydrocephalus were also reported.[513141516] Neuroimaging findings described in children with GA-I are frontotemporal atrophy, prominent Sylvian fissures with “bat wing appearance,” cortical atrophy, subdural effusions, signal changes in basal ganglia, and periventricular white matter.[17] Frontotemporal atrophy, prominent Sylvian fissures, and CSF spaces observed in our case might create a diagnostic dilemma with GA-I.

Although treatment with Vitamin B12 had resulted in a significant gain in gross motor and language domains, our patient was observed to have autistic traits during short-term follow-up. Short-term developmental gains following treatment with Vitamin B12 could be related to increase in cellular energy production or improved myelination.[18] Persistent unfavorable neurodevelopmental outcome has also been described.[19] A randomized control trial found that Vitamin B12 and folate supplementation had resulted in gains of gross motor and problem-solving skills, whereas there were no significant changes in fine motor, communication, and socio-personal skills.[18] However, there are reports of resolution of clinical symptoms after Vitamin B12 supplementation.[2021]

CONCLUSION

Vitamin B12 deficiency must be looked for as a cause of autistic regression or regression of milestones in children at risk for Vitamin B12 deficiency. Screening for Vitamin B12 deficiency must be considered in all infants and children with autistic regression, extrapyramdial signs or neuroregression, as this disorder is potentially treatable. Clinicoradiological picture in patients with infantile tremor syndrome may closely mimic GA-I. More population-based studies in India are needed to explore the prevalence of Vitamin B12 deficiency in pregnant women and lactating mothers. We also propose that Vitamin B12 supplementation in addition to folic acid must be considered in women during pregnancy and lactation at risk for Vitamin B12 deficiency.

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The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.