Neuropsychological and behavioral disorders as presentation symptoms in two brothers with early-infantile Niemann-Pick type C.

BACKGROUND: Niemann-Pick disease type C (NPC) is a lysosomal storage disease caused by mutations in NPC1 or NPC2 genes. CASE
PRESENTATION: We present two brothers with the same compound heterozygous variants in exon 13 of the NPC1 gene (18q11.2), the first one (c.1955C> G, p. Ser652Trp), inherited from the mother, the second (c.2107T>A p.Phe703Ile) inherited from the father, associated to the classical biochemical phenotype of NPC. The two brothers presented unspecific neurologic symptoms with difference in age of onset: one presented dyspraxia and motor clumsiness at age 7 years, the other showed a systemic presentation with hepatosplenomegaly noted at the age of two months and neurological symptoms onset at age 4 with speech disturbance. Clinical evolution and neuroimaging data led to the final diagnosis. Systemic signs did not correlate with the onset of neurological symptoms. Miglustat therapy was started in both patients.
CONCLUSIONS: We highlight the extreme phenotypic heterogeneity of NP-C in the presence of the same genetic variant and the unspecificity of neurologic signs at onset as previously reported. We report some positive effects of miglustat on disease progression assessed also with neuropsychological follow-up, with an age-dependent response.

Background

Niemann–Pick disease type C (NP-C) is a neurovisceral lysosomal storage disorder, characterized by intracellular accumulation of unesterified cholesterol and other compounds. Estimated incidence is 1:100.000. Clinical presentation is heterogeneous, encompassing progressive and disabling unspecific neurological symptoms. It is subdivided as pre/peri-natal (< 3 months), early-infantile (3 months–2 years), late-infantile (2–6 years), juvenile (6-15 years) and adolescent/adult (>15 years) based on neurological manifestations onset. In juvenile and adolescent-onset patients, intellectual disability, behavioral problems and attention-deficit hyperactivity disorder (ADHD) have been reported before the onset of neurological symptoms. Prognosis is generally poor (death in late teenage years/early adulthood). NP-C is caused by pathogenic variants in the NPC1 gene in 95% of cases, referred to as type C1 (OMIM*257220); 5% are caused by mutations in the NPC2 gene, referred to as type C2 (OMIM*607625), .

Miglustat, a reversible inhibitor of glucosylceramide synthase, is the first treatment approved for treating neurological complications in patients with NP-C. Its beneficial effects are limited in patients with the early-infantile form in advanced stages.

Case Presentation

Case Report 1

He is a 12-year-old boy born via caesarean section for fetal distress at 32 weeks (birth weight 1350 g). Family history was unremarkable.

At 7 years, visuo-spatial and learning difficulties were noted (dysgraphia, dyspraxia, and motor clumsiness). At 9 years, autism spectrum disorder was suspected due to poor eye contact and repetitive behavior.

He came to our attention at 9 years and 10 months with progressive cognitive impairment, memory disturbances, dyspraxia, gait abnormalities, episodes of transient loss of contact and abnormal saccadic eye movements.

Brain MRI showed cerebellar abnormalities, ventricular enlargement and white matter abnormalities (Figure 1). Biochemical analysis showed mild hypertransaminasemia (AST> 50 U/I), mild hypercholesterolemia (LDL>120 mg/dl), transient hypertriglyceridemia (203 mg/dl; 309 mg/dl). Splenomegaly was noted. NPC suspicion Index was 104 (high likelihood). At 10 years he had epileptic seizures, controlled on valproate.

Figure 1.

(A, B, C) Brain MRI of Patient 1at 10 years of age. Reduced volume of the cerebellum and vermis, more prominent superiorly, associated to a slight reduction of the superior and middle cerebellar peduncles with increased volume of the fourth ventricle and the cisterna magna (A, B), slight increase of the white matter signal intensity at the supratentorial level (C). (D, E, F): At 11 years and 6 months of age, mild worsening of the cerebellar atrophy at the level of the anterior cerebellar lobes (D, E). The periventricular white matter signal enhancement is more clearly delineated (F).

Molecular genetic testing by PCR sequencing on NPC1 gene revealed two heterozygous variants in exon 13, (c.1955C>G [Ser652Trp]), maternally-inherited and previously described and previously described, and (c.2107T>A [Phe703Ile]) paternally-inherited. Oxysterols 7-ketocholesterol elevation (310.5 ng/ml normal values: < 45.58 ng/ml) confirmed the diagnosis.

Six weeks after diagnosis, treatment with Miglustat was started (600mg/die). Follow-up after ten months revealed worsening of balance, speech apraxia and severe dysmetria. Some clinical parameters showed stabilization and improvement after 9 months of treatment. Prevention of dysphagia as well as improvement in attentional levels was noted. However, brain MRI, at 18 months follow-up, showed worsening of periventricular white matter signal and progression of cerebellar atrophy. At 12 years of age, cognitive profile shows multidomain cognitive impairment, with spared receptive vocabulary and comprehension of simplified sentences (see table 1).

Table 1.

Clinical data of our two patients

Neuropsychological follow-up of patient 1
Test and subtests	Timeline
	8 year and 3 month	9 years and 2 months
WISC-IV
Verbal Comprehension Index (VCI)	100
Perceptual Reasoning Index (PRI)	87
Working Memory Index (WMI)	64*
Processing Speed Index (PSI)	71*
IQ Score	77
Raven CPM		-1,5 SD
MMSP-E		-2 SD
BVN 5-11
Digit span		90
Word pairs learning		n.e.*
Word free recall		80
Word list - immediate recall		65*
Word list - delayed recall		65*
Attentional matrices		-2 SD
BVN 5-11
Reception of grammar		<60*
Semantic fluency		average
Phonemic contrast		-2 SD
DDE-2
Word reading (prova 2)	-1,76 SD*
Nonword reading (prova 3)	-2 SD*
Word writing (prova 6)	-2 SD*
Nonword writing (prova 7)	-2 SD*
BVSCO-2
Text writing	-2 SD*
MT
Text reading	-1,55 SD
Text comprehension	severe*
AC-MT
Calculations skills	borderline*
Knowledge of numbers	severe*
Accurancy	average
Time	severe*
Neuropsychological follow-up of patient 2
Test and subtests	Timeline
	7 years and 5 months	8 years and 8 months	11 years and 8 motnhs
WISC-IV			n.e.*
Verbal Comprehension Index (VCI)		86
Perceptual Reasoning Index (PRI)		67*
Working Memory Index (WMI)		73
Processing Speed Index (PSI)		47*
IQ Score		58*
WISC-III
Verbal IQ	112
Performance IQ	66*
IQ Score	88
Raven CPM			n.e.*
MMSP-E			n.e.*
BVN 5-12
Visual Span			<60*
Leiter-R
Attention sustained	average
MF
Average response time	+0.7 SD
Errors	-2.3 SD*
VMI
Motor coordination	70
Visual perception	48*
Visual-motor integration	severe*
BVN 5-12
Imitation of gestures			<60*
DDE-2			n.e.*
Word reading (prova 2)
Speed	-0.5 SD
Errors	-1.5 SD*
Word writing (prova 6)	-2.2 SD*
Nonword writing (prova 7)	-2.6 SD*
BVSCO-2			n.e.*
Text writing	-2.5 SD*
BHK			n.e.*
Speed	-1.5 SD*
Accurancy	-1.3 SD*
MT			n.e.*
Text comprehension	average
TROG-2
Reception of grammar			n.e.
Receptive vocabulary			average
AC-MT			n.e.*
Calculations skills	borderline*
Knowledge of numbers	average
Accurancy	average
Time	average

Case Report 2

Case 2, now 9 years-old, was born at 32 weeks (weight 1390 g). He presented axial hypotonia and neonatal jaundice. Aged 2 months, hepatosplenomegaly was detected. Motor development was normal. He was diagnosed with speech delay at 4 years and with learning disability at 8 years of age. He came to our attention at 8 years and 9 months of age showing mild dysarthria and impaired vertical saccades. Neuropsychological profile demonstrated multidomain cognitive impairment (see table 2). Bilateral sovra- and peritrigonal white matter hyperintensity in long TR sequences was detected on brain MRI at 9 years of age (figure 2). EEG showed bi-frontal slow sharp waves. Biochemical analysis showed mild hypertransaminasemia (AST 60U/I). Mild hepatosplenomegaly was diagnosed on abdominal ultrasound. Treatment with Miglustat (400mg/die) was initiated at 9 years and 2 months of age, after genetic confirmation of the same variants as his brother.

Figure 2.

A, B, C) Brain MRI of Patient 2: At 9 years of age, mild bilateral white matter hyperintensity in the sovra- and peritrigonal regions in long-TR sequences.

Discussion

We report on two brothers with juvenile and early infantile onset NPC harbouring the same compound heterozygous missense variants (c.1955C>G p.Ser652Trp) and (c.2107T>A Phe703Ile) in the NPC1 gene, resulting in different phenotypes and disease courses. The variant c.1955C> G, p. [Ser652Trp] has been previously described in homozigosity, associated with severe biochemical phenotype. However, detailed clinical information is unavailable and a severe clinical phenotype does not necessarily correlate with the severity of biochemical and genetic profile.

The variant c.2107T>A [Phe703Ile] to the best of our knowledge has not been previously reported. According to the American College of Medical Genetics and Genomics (ACMG), it fulfills the following points: PM1 (located in a mutational hot spot and/or critical and well-established functional domain) PM2 (absent in gnomAD control population), PM5 (novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before) PP2 (missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease), PP3 (multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.): thus classified as likely pathogenic.

In both cases a sneaky neurologic debut was present in childhood. However, neonatal jaundice and persistent splenomegaly might be considered the first symptoms, thus implying a neonatal/early-infantile onset.

Both cases confirm that timing of systemic symptoms onset does not correlate with neurological onset. Otherwise, age at neurological symptoms onset is associated with disease progression severity.

Phenotypic variability has been previously described in sibilings. Furthermore, two monozygotic twins carrying the same homozygous causative variant have been described: one had an adult late-onset form, the second isolated splenomegaly. It is possible to speculate that this variability might depend on modifier genes and epigenetic interaction-.

Phenotypic heterogeneity is misleading in differential diagnosis with other child neuropsychiatric disorders including learning disorders, autism, speech delay, behavior, mood and thoughts disorders, with a risk for delay in diagnosis.

Impairment in cognitive functions markedly correlates with age at therapy initiation. Many authors also demonstrated that Miglustat stabilizes or might improve neurological signs.

Conclusions

We presented two brothers with the same genotype but a different neurological picture, confirming extensive clinical heterogeneity and absence of clear genotype-phenotype correlations in NPC1.

We recommend to consider NP-C in unspecific neuropsychiatric disorders, especially in progressive cases, and never underestimate isolated or persistent hepatosplenomegaly/splenomegaly, or eye movements abnormalities.

Early diagnosis is crucial for a timely pharmacological intervention, in order to prevent irreversible neurological damage and thus change the course of the disease, improve patients’ quality of life and extend life expectancy.

Neuropsychological scores and description of tests are extensively reported in Supplementary Material 1.

American College of Medical Genetics and Genomics.

aspartate aminotransferase;

electroencephalogram;

low density lipoprotein;

magnetic resonance imaging;

Niemann Pick type C;

Niemann Pick type C 1;