Clinical manifestations and molecular genetics of seven patients with Niemann–Pick type-C: a case series with a novel variant

Case 1

A 3-day-old male patient was referred to our outpatient clinic on the third postpartum day with jaundice and an enlarged abdominal circumference (Figure 1A).

Figure 1:

Clinical and imaging findings in two cases. (A) Case 1 presenting with jaundice and an enlarged abdominal circumference suggestive of underlying hepatic involvement. (B) High-resolution chest computed tomography (HRCT) scan of Case 2 showing ground-glass opacity and interlobular septal thickening in both lungs, indicative of pulmonary involvement. (C) Milky bronchoalveolar lavage fluid from Case 2, characteristic of pulmonary alveolar proteinosis (PAP).

He was born at term by cesarean delivery with a birth weight of 3,135 g, and his medical history revealed that increased abdominal circumference and hepatosplenomegaly had been identified during the intrauterine period. The patient was the second child of consanguineous parents, although both the parents and sibling had an unremarkable medical history.

A physical examination at the time of admission revealed mild jaundice, hepatosplenomegaly, and hypotonia, while all other system examination results were normal.

Laboratory tests revealed elevated serum levels of aspartate aminotransferase (AST): 298 U/L [reference range (RR): 0–50], alanin aminotransferase (ALT): 82 U/L (RR: 0–50), total bilirubin (T.bil): 9.4 mg/dL (RR: 0.1–1.2), and direct bilirubin (D.bil): 6.5 mg/dL (RR: 0.0–0.3). Activated partial thromboplastin time (APTT), international normalized ratio (INR), and albumin level were all normal, and complete blood count, serum electrolytes, renal function test, and plasma ammonia level results were all within the normal range. Carnitine/acylcarnitine profile, plasma amino acids analysis, and urinary organic acid analysis were unremarkable. An abdominal ultrasonography revealed hepatosplenomegaly.

The clinical and laboratory findings of cholestatic liver disease led the patient to be investigated for lysosomal storage disorders, and an elevated lysoSM-509 level [936 nmol/L (RR: 1.0–33.0)] was detected. A genetic investigation revealed a homozygous c.2039dupT (p.L680Ffs*9) pathogenic variant in the NPC1 gene.

Following the diagnosis of NPC, the patient was started on a course of ursodeoxycholic acid and 25-hydroxyvitamin D, but the patient’s condition rapidly deteriorated, resulting in multiorgan failure and subsequent death at 138 days of age.

Case 2

A 3-month-old female patient presented with a complaint of jaundice that had manifested at the age of 2 days. The patient was born at term with a normal pregnancy. The patient’s parents were of consanguineous descent.

The patient was identified with hypotonia, hepatosplenomegaly, and poor motor development on physical examination, and laboratory tests revealed elevated ALT, AST levels, and D. bil, while their carnitine/acylcarnitine profile, plasma amino acid, and urinary organic acid analysis results, very-long-chain fatty acid and chitotriosidase levels were all normal.

During clinical follow-up, the patient was intubated at 3 months of age due to respiratory failure. A high-resolution chest computed tomography (HRCT) scan revealed ground-glass opacity and interlobular septal thickening in both lungs (Figure 1B), while bronchoalveolar lavage fluid was milky, and examination of this fluid revealed findings consistent with typical pulmonary alveolar proteinosis (PAP) (Figure 1C).

A diagnosis of Niemann–Pick disease type C was considered based on the findings at presentation, which included hypotonia, jaundice, hepatosplenomegaly, and pulmonary involvement, and a genetic analysis revealed a homozygous c.434 T>A (p.Val145Glu) pathogenic variant in the NPC2 gene.

A hematopoietic stem cell transplantation (HSCT) was arranged, but the patient died at the age of 8 months due to progressive respiratory failure.

Case 3

An 8-day-old female infant was referred to our center for further investigation due to her history of a sibling (Case 2) who had died as a result of NPC.

The patient, born following a term pregnancy with a weight of 3,500 g, was the fourth child of consanguineous parents, the first of which (Case 2) had been diagnosed with NPC. The patient exhibited progressive jaundice on the fifth postpartum day, necessitating hospitalization in a different medical center until the age of 8 days.

A physical examination revealed jaundice accompanied by hepatosplenomegaly, while a laboratory investigation revealed hyperlactatemia, elevated transaminases (AST: 211 U/L, ALT: 82 U/L), T. bil: 4.18 mg/dL, D. bil: 2.3 mg/dL, and elevated alpha fetoprotein (AFP) levels (>10,000 ng/mL). The patient’s plasma ammonia level, carnitine/acylcarnitine profile, plasma amino acids analysis, and urinary organic acid analysis were all unremarkable.

The patient was assessed for NPC disease, revealing the presence of lysoSM-509 at a concentration of 1,101 nmol/L (RR: 1.0–33.0) and an elevated lysoSM-509/lysoSM ratio, with a value of 135.9 (RR:1.7–28). A genetic analysis conducted due to the family history of a sibling diagnosed with NPC revealed a homozygous c.434 T>A (p.Val145Glu) pathogenic variant in the NPC2 gene. The patient was treated with ursodeoxycholic acid and vitamins and was also administered miglustat therapy.

Following a clinical evaluation, HSCT was scheduled; however, the patient’s condition deteriorated rapidly, resulting in multiorgan failure and subsequent death at the age of 103 days.

Case 4

A female patient was referred to our center with acute liver failure and hepatomegaly that developed at the age of 6 months, prior to which she had exhibited no specific findings. She was born via spontaneous vaginal delivery as the fourth child of parents who were first-degree cousins and was thus investigated for inherited metabolic disorders. A physical examination revealed the presence of hepatosplenomegaly.

Laboratory tests revealed elevated serum levels of AST (329 U/L), ALT (62 U/L), T. bil (4.4 mg/dL), and D. bil (1.89 mg/dL), while her activated partial thromboplastin time (APTT), international normalized ratio (INR), and alpha-fetoprotein (AFP) levels were above the normal range. The patient’s blood ammonia level, infectious markers, blood amino acid spectrum analysis, and urinary organic acid analysis were all found to be within the normal range.

Abdominal ultrasonography revealed findings consistent with chronic liver disease, splenomegaly, and diffuse ascites, and bone marrow aspiration was conducted to ascertain the diagnosis of lysosomal storage disease, revealing sea-blue histiocytes and elevated chitotriosidase enzyme levels.

The genetic analysis revealed a homozygous c.2009G>T (p.Cys670Phe) pathogenic variant in the NPC1 gene. Following 2 weeks of observation in the pediatric intensive care unit, the patient was transferred to another clinic at the request of her family.

Case 5

A 3-month-old male infant was referred to our intensive care unit after developing liver failure, at which time he was identified with abdominal distension.

The infant had been delivered at full term (39 weeks, 3,790 g) to second-degree consanguineous parents and developed jaundice on the third day of life.

The patient was admitted to hospital at the age of 70 days with wheezing and retractions, and a physical examination revealed hepatomegaly, splenomegaly, and abdominal distention, at which time he was referred to our clinic for an assessment of potential inherited metabolic diseases due to his family history and the clinical features.

Laboratory tests revealed elevated aminotransferases (AST: 1029 U/L, ALT: 400 U/L) and bilirubin levels (T.bil: 4.55 mg/dL, D. bil: 4.13 mg/dL), while his ammonia and lactate levels were within the normal range, and a lysosphingolipid analysis revealed elevated lysoSM-509: 869.4 nmol/L (RR: 1.0–33.0) and lysoSM-509/lysoSM: 126 (RR: 1.7–28).

A genetic analysis of the NPC1 and NPC2 genes was conducted, revealing a novel homozygous c.315del p (Thr106ProfsTer5) variant in the NPC1 gene that was class 2 (likely pathogenic) according to the American College of Medical Genetics (ACMG) criteria.

Thorax computed tomography (CT) scans during clinical follow-up revealed central ground-glass densities and interlobular central thickening that were attributed to the pulmonary involvement of the disease.

Treatment with miglustat was initiated to mitigate the neurological effects, and the patient remains under palliative care in our clinic. In the clinical follow-up, regression of cholestasis was observed and he is currently 1 year old.

Case 6

A 31-year-old woman presented with concerns about behavioral changes and poor academic performance at age 13.

The subject was born after a full-term pregnancy, and her parents were unrelated. The child’s development was consistent with typical milestones for the age group up to age nine.

Sudden head drop during downward gaze was first noted at age nine, and by age 13, poor academic performance, behavioral changes, and an ataxic gait began (Supplementary video).

A diagnosis of vertical supranuclear gaze paralysis was made following a physical examination. Electroencephalography (EEG) has revealed the presence of epileptic abnormalities in bilateral frontal regions. Cranial magnetic resonance imaging (MRI) has demonstrated cerebral atrophy and widening of the lateral ventricles.

The patient was assessed for the possibility of an inherited metabolic disease, skin biopsy showed negative Filipin staining, and no pathogenic variant was detected in the NPC1 gene. Nevertheless, the patient’s complaints continued to progress. The patient who had a sibling (Case 7) with similar neurological symptoms and diagnosed with NPC was reassessed. Despite normal chitotriosidase activity, lysosphingolipid analysis revealed the presence of lysoSM-509 at 644.78 nmol/mL (RR: 1.00–33.00) and lysoSM-509/lysoSM at 843.4 (RR: 1.7–28). A genetic analysis was conducted, revealing the presence of a homozygous c.358 C>T (p.Pro120Ser) pathogenic variant in the NPC2 gene.

Miglustat treatment initiated following diagnosis led to precipitated episodes of unwarranted anger, suspicious behavior, delusions, seizures, contractions in the hands, and myoclonus in the extremities during sleep, and so the treatment was discontinued. In the subsequent follow-up period, a notable decline was noted in the psychiatric symptoms, but an observable progression in neurological impairment.

Case 7

A 25-year-old female patient who had been followed up since the age of 15 years with a diagnosis of NPC presented to our center after developing symptoms of dementia, seizures, and ataxia at the age of 14 years, and vertical ocular apraxia 1 year later.

The patient born at term with a birth weight of 3,500 g to nonconsanguineous parents. Her initial symptoms started at the age of 6 years with social isolation, and at the age of 9 years, she suddenly started experiencing attacks of dizziness, followed by a decline in academic achievement 1 year later, accompanied by a long-term decline in psychomotor skills and apathy.

The results of clinic biochemical and metabolic laboratory tests performed in our center were all within the reference range, while abdominal ultrasonography revealed hepatomegaly and hepatosteatosis. Bone marrow aspiration was performed due to suspicions of lysosomal disease, but no sea-blue histiocytes were detected. Cranial MRI revealed cerebral/cerebellar atrophy and signal abnormalities in the periventricular white matter, while an electroencephalogram revealed an epileptic anomaly in the bilateral frontal region. A hearing test was unremarkable.

The results of a lysosphingolipid analysis were lysoSM-509:674.78 nmol/mL and lysoSM-509/lysoSM: 843.4. Since the patient’s findings indicated a high probability of NPC, a genetic study was performed revealing a homozygous c.358 C>T (p.Pro120Ser) pathogenic variant in the NPC2 gene.

Miglustat treatment was started after diagnosis and continued for 6 months but caused sudden bursts of anger and delusions in the patient, and these neuropsychiatric symptoms led to the discontinuation of the treatment. The psychiatric findings decreased during follow-up; however, there was progression in the neurological impairment. In the roughly 7 years since the discontinuation of miglustat treatment, the patient has experienced no psychotic episodes.