Adult onset Niemann–Pick type C disease: Two different presentations
Niemann–Pick disease Type C (NPC) is a rare lysosomal storage disorder of autosomal recessive inheritance. It is characterized by neuro-visceral manifestations. The main defects occur due to accumulation of unesterified cholesterol and glycolipids within the lysosomal system., The pattern in which the lipids accumulate within the tissues is different in the brain and in non-neural organs. Two genes are found to be affected. The most common are mutations in the NPC 1 gene (18q11), seen in 95% of patients. This gene encodes a large membrane glycoprotein which localizes in late lysosomes. The rest have mutations in the NPC2 gene (14q24.3), which encodes a high-affinity cholesterol binding a small soluble lysosomal protein.,
The NPC1 and NPC2 genes have a nonredundant functional cooperativity. The two proteins either function in tandem or in sequence. Their main function appears to be related to postlysosomal transport of cholesterol, glycolipids, and other molecules. However, their precise functions, mechanisms and interactions remain unclear with an elusive primary substrate.,, Currently, NPC is biochemically diagnosed by demonstrating impaired low-density lipoprotein (LDL)-cholesterol trafficking in cultured fibroblasts of patients. Filipin stain is used on these cultured fibroblasts to visualize the accumulated free cholesterol and also to study the LDL-induced cholesterol ester formation.
The epidemiology of this disease in India is not known as yet. This is a rare disease and the adult form of this disease is rarer still. However, the disease may be underdiagnosed due to its highly heterogeneous presentation. The presentations of these cases are varied and there are no fixed criteria for the diagnosis of this disease. We attempt to critically analyze both our patient's symptomatology and investigational findings which may help in establishing a better diagnosis of this entity in the future.
The first patient, a forty-year-old male patient, a product of nonconsanguineous marriage, residing at a remote village of West Bengal, cultivator by profession, presented with several neurological signs and symptoms. All his troubles began 1½ years back when he experienced progressive anosmia. This was followed by the onset of slurring of speech, difficulty in deglutition to both liquid and solid food material, and occasional abnormal posturing of the distal part of upper limbs ½ year later. He also developed a tendency to fall while walking, 6 months later. All these events were insidious in onset and slowly progressive in nature.
There was no history of unconsciousness, seizures, headache, or memory impairment. The patient had no complaints regarding either limb weakness, subjective sensory impairment or cranial nerve involvement. The bowel and bladder functions were normal and there was neither associated weight loss nor fever. The patient was nonhypertensive and nondiabetic.
His general examination was normal. Neurological examination revealed a dysarthric speech, with imprecise consonants. The spine and cranium were normal and there were no signs of meningeal irritation. Upon conducting a cranial nerve examination, it was found that bilateral olfactory nerves were affected leading to diminished olfaction. Another finding was the presence of vertical gaze palsy (with downward gaze restriction greater than upward gaze restriction). There was no nystagmus present. Rest of the cranial nerves were normal.
His bilateral upper limbs showed features of dystonia without the presence of any atrophy. An ataxic gait and tandem walking impairment were also found. The power of all 4 limbs was, however, normal. Sensory examination of both spinothalamic and dorsal column sensations was within normal limits. Reflexes and cerebellar functions were normal. The systemic examination was normal except for the presence of a mild splenomegaly.
All laboratory investigations were noncontributory. No Kayser–Fleischer ring was found. Ultrasonography of the whole abdomen revealed mild splenomegaly. Magnetic resonance imaging (MRI) of the brain showed global diffuse cerebral and mild cerebellar atrophy [Figure 1]. A bone marrow aspiration showed sea-blue histiocytes on microscopic examination [Figure 2].
Our second patient was a 23-year-old unmarried, nondiabetic, and nonhypertensive male patient, a product of nonconsanguineous marriage, without any positive family history, hailing from an urban area of West Bengal, who, after a normal childhood and adolescence, presented with dysphagia of 2 years duration. This was followed by inability to talk along with limb movement restrictions for the past 1 year. The dysphagic symptoms were insidious in onset, were gradually progressive in nature, and were present for both solid and liquid food materials. Nasal regurgitation was also present. There was no diurnal variation. No history of any odynophagia was found. His mother complained that for the past 2 years, he had shown occasional irritability and emotional lability. He also had an episodic memory loss. The dysarthric manifestations were also insidious in onset with gradual progression. He was unable to complete sentences and pronounce each word discretely. Abnormal posturing of all the limbs with tremor was present for the same duration as dysarthria. Distal parts showed more significant manifestations than the proximal parts.
The patient has no past history of any other illness. He was nondiabetic and nonhypertensive. No history of chronic nerve involvement was found. His bladder and bowel habits were normal. He was the eldest of three siblings. Other siblings did not have similar neurological manifestations. Furthermore, no family history of a similar presentation was found.
The general examination was unremarkable. No organomegaly was found. On detailed nervous system examination, there was decreased facial expression. Vertical gaze palsy was present but horizontal gaze was normal. Neither saccadic eye movements nor a Kayser–Fleischer ring were found. Motor examination revealed dystonia for all the four limbs and neck muscles. There was associated rigidity, bradykinesia, and postural tremors. The sensory examination was unremarkable. Plantar reflexes of both sides were not manifesting while the jaw jerk was brisk. Rest of the reflexes were normal. Cerebellar examination revealed no abnormality.
Investigations done were complete blood count (CBC), bone marrow biopsy and MRI of the brain. CBC was within normal limits. Foamy sea-blue histiocytes were found on bone marrow aspirate and biopsy [Figure 3]. Periodic acid-Schiff stain of the bone marrow aspirate was weakly positive. MRI of the brain was normal [Figure 4].
Neimann–Pick disease is a group of familial lysosomal storage disorders and has three types. Types A and B have a deficiency of the enzyme, sphingomyelinase. This leads to a build-up of sphingomyelin in cells. The gene sphingomyelin phosphodiesterase 1 (SMPD1), located on chromosome 11p15.1–p15.4, undergoes mutation, which is either a deletion or missense mutation. Type A disorder is more severe than the Type B one. This is because the Type A disorder has neurological symptoms unlike the Type B disorder and usually appears at infancy.
NPC is a rare lysosomal storage disorder which is usually fatal and affects both children and adults. The disease in children is characterized by mental retardation, seizures and often a rapid neurodegeneration, while adults present with a slow cognitive decline, a major neuropsychiatric illness, and the development of ataxia and dystonia. NPC is a complex disease that first of all affects the spleen, liver, and brain, resulting in visceral abnormalities as well as neurological and psychiatric manifestations. These changes are progressive in nature. The incidence of dysphagia in adult onset NPC is about 37%, psychiatric disorders is 45%, movement disorders is 58%, cognitive troubles is 61%, dysarthria is 63%, and vertical supranuclear ophthalmoplegia is 75%.
The prevalence in India is not known but in western countries it varies from one in 5,00,000 to one in 7,50,000. There usually a mean delay in diagnosis of about 6.4 years. The main reason of the delay is due to both the rarity of the disease and its heterogeneous presentation.
Analyzing the symptomatology in both our patients, the primary affected regions appeared to be brain stem, midbrain, and the extra-pyramidal system. The first patient has additional involvement of the olfactory tract and cerebellum. After thoroughly negating all the possible differential diagnosis, the bone marrow study was advised based on our strong suspicion. The results showed that NPC might not be as rare as it might appear to be and is often missed as it is not considered in the differential diagnosis.
Oropharyngeal dysphagia, as seen in our patients, may have several differential diagnosis which may include structural defects, or, neurological or myogenic problems. The main ones include Parkinson's disease (bradykinesia and dyskinesia affecting all the phases), multiple sclerosis (mainly pharyngeal phase affected), Huntington's disease (dyspagia is mainly seen for liquid food), cerebral palsy (mainly associated with severe cases), vascular accidents, Guillain–Barre Syndrome, amyotrophic lateral sclerosis (due to hyper-reflexic and hypertonic effects), post-poliomyelitis syndrome, and the presence of a brainstem tumor.
The vertical gaze palsy is caused due to damage to the premotor structures in the midbrain, namely the rostral interstitial nucleus of the medial longitudinal fasciculus and the interstitial nucleus of Cajal. Its differential diagnosis includes lysosomal storage disorders such as GM2 gangliosidosis; mitochondrial diseases, chronic progressive external ophthalmoplegia, Kearns–Sayre Syndrome, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); muscular dystrophies such as myotrophic dystrophy, oculo-pharyngeal dystrophy; motor system disorders such as Parkinson's disease; enzyme deficiency diseases such as Huntington's disease and Wilson's disease; degenerative diseases such as progressive supranuclear palsy, corticobasal degeneration, ataxia telangiectasia; manifestations secondary to other diseases such as Whipple's disease, kernicterus, Sylvian aqueduct syndrome, Huntington's chorea, and neuro-acanthocytosis.
Dysarthria with dystonic features may be seen in Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, etc., All other causes could be eliminated based on the fact that in our patients, the MRI scan of the brain showed only global atrophy, and there was the presence of sea-blue foamy histiocytes in the bone marrow. Other causes of sea-blue histiocytes which mainly include lysosomal storage disorders do not produce the entire spectrum of neurological and psychiatric manifestaitons seen in our patients.
The limitations of our case report were the inability to perform an enzymatic study to exclude Gaucher's disease and Niemann–Pick Type B disease. Furthermore, genetic study and fibroblastic culture could not be done. In spite of the limitations, we could provisionally diagnose both our cases on the basis of their clinical presentation and investigational findings.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]