From the Genetic Clinic, Department of Pediatrics, Seth GS Medical College & KEM Hospital, Parel, Mumbai 400 012, and *Laboratory of Molecular Oncology, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Andhra Pradesh, India.

A female infant born of an inbred consanguineous union presented at one year of age with developmental delay and loss of developmental skills. The antenatal period and labor was uncomplicated. Birth weight was 2.75 kg. Poor feeding and weak cry were noted in the first week of life. Social smile was attained at 3 months, by 4 months, she was grasping and visually tracking objects and turning her head towards sounds. At 6 months, the child was lethargic and feeding poorly with no neck control. At 8 months, the social smile was lost and at 9 months, there was loss of roll over, stranger anxiety, visual tracking, and response to sound. There was no history of seizures, involuntary movements, abnormal limb posturing, hyperacusis, abnormal increasing in head size or abdominal distention. Due to hypotonia and joint stiffness at 9 months of age, electromyogram at another hospital had shown a myopathic pattern. Nerve conduction, thyroid hormone levels and creatinine phosphokinase were normal. MRI revealed severe generalized cerebral atrophy, dilatation of the supratentorial ventricular system, widened basal cisterns and atrophic corpus callosum. BERA showed right sided severe sensorineural hearing loss and left sided mild hearing loss. On examination at one year of age, the weight, height and head circumference were all below the 5th percentile. Flexion contractures of the elbow, hip, knee, metacarpophalangeal and interphalageal joints were present. There were multiple, firm, subcutaneous nodules measuring 0.5 to 1 cm in diameter over the knee joints and metacarpophalangeal and interphalangeal joints of the feet. The voice was weak and hoarse. Bilateral cherry red spot were detected. The child was irritable, not responding to commands and vocalization was absent. There was generalized hypertonia, power was 3/5, deep tendon reflexes were hypoactive, plantar response was flexor, menace reflex was absent and there was no response to sound. Coarse facies, hepatosplenomegaly and hernias were absent. Farber disease was suspected but the family declined to pursue investigations due to financial constraints and there was no follow-up.

The spectrum of manifestations in FD range from the most severe presenting as hydrops fetalis, neonatal onset (type 4), early infantile onset variant (classic or type 1), and progressive neurological form (type 1) to the milder phenotypes (type 2 and 3) [1]. Four cases of FD have been reported from India in the past 20 years [2, 3]. Seventeen ASAH 1 mutations have been reported to date worldwide [4]. Of these, 12 were missense mutations, two were intronic splice site mutations leading to exon skipping, and one each was a small insertion and deletion. This includes one other mutation reported in an Indian patient apart from the present [3]. All these are private mutations. It is a custom in many regions of the world including India to preserve the umbilical cord [5,6]. DNA has been extracted from umbilical cords preserved for up to 44 years for forensic investigations [5].

Elevation of plasma chitotriosidase has not been reported earlier in FD. Chitotriosidase is a chitinase expressed by activated macrophages [10,11]. More than 1000 fold elevations are observed in Gaucher disease. Chitotriosidase acivity is also increased in several other lysosomal diseases as well as in diseases like glycogen storage disease type IV, Alagille disease, arteriosclerosis, β-thalassemia major, sarcoidosis and malaria [10,11]. Our case adds to the spectrum of lysosomal storage disorders with increased chitotriosidase activity. However, it is also possible that the nearly 10 fold elevation in our patient could be secondary to intercurrent infection as the enzyme level is high in bacterial and fungal infections due to inflammatory cytokines that augment production [11].

In conclusion, though manifestations of FD are unique, diagnosis can be delayed if symptoms are misinterpreted. Without the availability of acid ceramidase activity testing in India, tissue biopsy is diagnostic. However, availability of genotyping in India may replace the need for invasive histopathological diagnosis. DNA banking is an urgency in circumstances where mortality in genetic disease like FD is early and unpredictable. This report serves to raise awareness amongst physicians for the need to preserve DNA in cases of suspected fatal genetic diseases.

Acknowledgments: The authors thank Dr Sanjay Oak, Director of Medical Education & Health for granting permission to publish this paper and Dr Chitra Prasad, Associate Professor of Genetics, Metabolism and Pediatrics, London, Ontario for her inputs.

Contributors: SA drafted the paper and performed literature search, MM diagnosed and investigated the case and revised the paper, KL provided intellectual inputs, MB performed the molecular analysis.

Funding: None; Competing interests: None stated.

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