Late Infantile Metachromatic Leukodystrophy Due to Novel Pathogenic Variants in the PSAP Gene

Kolníková, Miriam; Jungová, Petra; Škopková, Martina; Foltan, Tomas; Gašperíková, Daniela; Mattosova, Slavomira; Chandoga, J

doi:10.1007/s12031-019-1259-7

Cited by 16 publications

(16 citation statements)

References 27 publications

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“…Correlation with their remaining activity is missing, and even normal activity of single sulfatases occurs 1,2,7‐9 . Deficiency of arylsulfatase A (ARSA) (EC 3.1.6.8) (also due to pathogenic variants in ARSA or PSAP revealing metachromatic leukodystrophy [MLD; OMIM #250100] or SAP‐B deficiency [SAP‐B; OMIM #249900]) leads to accumulation of sulfatides causing neurodegeneration 10 . Severe ARSA deficiency is a relatively constant finding in MSD causing MLD‐typical features with neurological symptoms (like spasticity, tremor, ataxia, or dysphagia) and loss of skills, both phenomena characterizing mainly the later disease stage 11 .…”

Section: Introductionmentioning

confidence: 99%

“…1,2,[7][8][9] Deficiency of arylsulfatase A (ARSA) (EC 3.1.6.8) (also due to pathogenic variants in ARSA or PSAP revealing metachromatic leukodystrophy [MLD; OMIM #250100] or SAP-B deficiency [SAP-B; OMIM #249900]) leads to accumulation of sulfatides causing neurodegeneration. 10 Severe ARSA deficiency is a relatively constant finding in MSD causing MLD-typical features with neurological symptoms (like spasticity, tremor, ataxia, or dysphagia) and loss of skills, both phenomena characterizing mainly the later disease stage. 11 Deficiency of other sulfatases can result into dysmorphism, organomegaly, or dysostosis multiplex, resembling different mucopolysaccharidoses, like mucopolysaccharidosis II (M. Hunter; OMIM #309900), IIID (M. Sanfilippo-D; OMIM #252940), or VI (Maroteaux-Lamy-Syndrom; OMIM #253200) for example due to deficiency of iduronate-2-sulfatase (EC 3.1.6.13), N-acetylglucosamine-6-sulfatase (EC 3.1.6.14), or arylsulfatase B (ARSB) (EC 3.1.6.12), respectively.…”

Section: Introductionmentioning

confidence: 99%

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Long‐term disease course of two patients with multiple sulfatase deficiency differs from metachromatic leukodystrophy in a broad cohort

et al. 2020

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Multiple sulfatase deficiency (MSD) is a lysosomal storage disease caused by a deficiency of formylglycine‐generating enzyme due to SUMF1 defects. MSD may be misdiagnosed as metachromatic leukodystrophy (MLD), as neurological and neuroimaging findings are similar, and arylsulfatase A (ARSA) deficiency and enhanced urinary sulfatide excretion may also occur. While ARSA deficiency seems a cause for neurological symptoms and later neurodegenerative disease course, deficiency of other sulfatases results in clinical features such as dysmorphism, dysostosis, or ichthyosis. We report on a girl and a boy of the same origin presenting with severe ARSA deficiency and neurological and neuroimaging features compatible with MLD. However, exome sequencing revealed not yet described homozygosity of the missense variant c.529G > C, p.Ala177Pro in SUMF1. We asked whether dynamics of disease course differs between MSD and MLD. Comparison to a cohort of 59 MLD patients revealed different disease course concerning onset and disease progression in both MSD patients. The MSD patients showed first gross motor symptoms earlier than most patients with juvenile MLD (<10th percentile of Gross‐Motor‐Function in MLD [GMFC‐MLD] 1). However, subsequent motor decline was more protracted (75th and 90th percentile of GMFC‐MLD 2 (loss of independent walking) and 75th percentile of GMFC‐MLD 5 (loss of any locomotion)). Language decline started clearly after 50th percentile of juvenile MLD and progressed rapidly. Thus, dynamics of disease course may be a further clue for the characterization of MSD. These data may contribute to knowledge of natural course of ultra‐rare MSD and be relevant for counseling and therapy.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Long‐term disease course of two patients with multiple sulfatase deficiency differs from metachromatic leukodystrophy in a broad cohort

et al. 2020

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“…1 PSAP mutation, causing MLD, is relatively uncommon with 11 causative mutations being identified globally. 2,4 This report illustrates a child with PSAP mutation who presented initially as acute flaccid paralysis (demyelinating polyneuropathy) but gradually evolved into a leukodystrophy. Gall bladder polyposis was an interesting extraneural finding.…”

Section: Discussionmentioning

confidence: 94%

“…Saposin B protein is one of the four cleavage products (saposins A, B, C, and D) derived from the 524 amino-acid precursor protein encoded by the prosaposin gene (PSAP). 2 Hereby we report a child with acute onset of flaccid paralysis who was later diagnosed to have saposin B-deficient late infantile MLD.…”

Section: Introductionmentioning

confidence: 93%

“…However, this variant has recently been reported in a compound heterozygous state with another variant-c.1268delT (p.Leu423Argfs Ã 40) in a patient with late infantile MLD. 2 The in silico predictions of the variant were damaging by Mutation Taster2, SIFT, and Polyphen2 and the reference codon is conserved across species. Hence, this PSAP variation was likely pathogenic.…”

Section: Introductionmentioning

confidence: 99%

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Saposin B–Deficient Metachromatic Leukodystrophy Mimicking Acute Flaccid Paralysis

et al. 2019

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Metachromatic leukodystrophy (MLD) is a rare sphingolipid storage disorder caused by arylsulfatase A (ARSA) deficiency, resulting in central and peripheral demyelination. However, an uncommon form of MLD caused by saposin B deficiency is also described (around 10 mutations reported till date). MLD is a systemic disorder affecting the central and peripheral nervous system, gall bladder, and kidneys. Acute flaccid paralysis as the initial clinical presentation is previously known in ARSA-deficient MLD. Hereby, we report a child with acute flaccid paralysis with brain magnetic resonance imaging showing nonspecific periventricular leukodystrophy. He had progressive cognitive decline with gall bladder polyposis. ARSA levels were within normal limits. Leukodystrophy gene panel revealed a homozygous pathogenic deletion (Lys227del variant) in prosaposin (PSAP) gene. Hence, a final diagnosis of saposin B–deficient MLD was established. The index case highlights the importance of clinical and electrophysiological clues in the diagnosis of such atypical presentations of MLD.

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Late infantile and adult‐onset metachromatic leukodystrophy due to novel missense variants in the PSAP gene: Case report from India

et al. 2023

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Metachromatic leukodystrophy (MLD) due to Sap-B deficiency is a rare autosomal recessive disorder caused due to biallelic variants in the PSAP gene. The PSAP gene encodes a precursor protein prosaposin, which is subsequently cleaved to form four active glycoproteins: Sap-A, Sap-B, Sap-C, and Sap-D. In case of deficiency of the sphingolipid activator protein Sap-B, there is a gradual accumulation of cerebroside-3-sulfate in the myelin of the nervous system resulting in progressive demyelination. Only 12 variants have been reported in the PSAP gene causing Sap-B deficiency to date. Here, we report two cases of MLD due to Sap-B deficiency (late-infantile and adult-onset form) harboring two novel missense variants c.688T > G and c.593G > A in the PSAP gene respectively. This study reports the third case of adult-onset MLD due to Sap-B deficiency in the world. The proband, a 3-year-old male child presented with complaints of hypotonia, lower limb tremors and global developmental delay. His MRI showed hyperintense signals in the bilateral cerebellar white matter. Overall, the findings were suggestive of metachromatic leukodystrophy. The second case was a 19-year-old male child with clinical features of regression of speech, gait ataxia and bilateral tremors referred to our clinic. MRI data suggested metachromatic leukodystrophy. Normal enzyme activity of arylsulfatase-A led to a suspicion of saposin B deficiency. For both cases, targeted sequencing was performed. This identified homozygous variant c.688T > G (p.Cys230Gly) and c.593G > A (p.Cys198Tyr) in exon 6 of the PSAP gene, respectively.

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Late Infantile Metachromatic Leukodystrophy Due to Novel Pathogenic Variants in the PSAP Gene

Cited by 16 publications

References 27 publications

Long‐term disease course of two patients with multiple sulfatase deficiency differs from metachromatic leukodystrophy in a broad cohort

Long‐term disease course of two patients with multiple sulfatase deficiency differs from metachromatic leukodystrophy in a broad cohort

Saposin B–Deficient Metachromatic Leukodystrophy Mimicking Acute Flaccid Paralysis

Late infantile and adult‐onset metachromatic leukodystrophy due to novel missense variants in the PSAP gene: Case report from India

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