Expanding the Spectrum of <scp><i>AP5Z1‐</i></scp>Related Hereditary Spastic Paraplegia (<scp>HSP‐SPG48</scp>): A Multicenter Study on a Rare Disease

Breza, Marianthi; Hirst, Jennifer; Kobylecki, Christopher; Banneau, Guillaume; Tissier, Laurène; Kol, Bophara; Bourinaris, Thomas; Péreón, Yann; Heinzmann, Anna; Debs, Rabab; Juntas-Moralès, Raul; Martinez, V.; Camdessanché, J.-P.; Scherer-Gagou, Clarisse; Zola, Jean-Médard; Athanasiou-Fragkouli, Alkyoni; Efthymiou, Stéphanie; Vavougios, George D.; Velonakis, Georgios; Stamelou, María; Tzartos, John; Potagas, Constantin; Mariotti, Caterina; Blackstone, Craig; Vandrovcová, Jana; Mavridis, Theodoros; Kartanou, Chrisoula; Stefanis, Leonidas; Wood, Nicholas W.; Karadima, Georgia; LeGuern, Eric; Houlden, Henry; Stevanin, Giovanni

doi:10.1002/mds.28487

Cited by 9 publications

(6 citation statements)

References 7 publications

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“…Among forms affecting directly the autophagy and lysosomal pathways, miglustat was succefully used to reduce ganglioside accumulation in SPG11 zebrafish models (Boutry et al, 2018), and tideglusib, a GSK3b inhibitor, prevented the neurite pathology in brain organoids of SPG11 patients (Pozner et al, 2018). Autophagy regulators might also be of interest in SPG48 (Breza et al, 2021) and rapamycin partially reversed the phenotype induced by Atlastin-1 loss of function in flies (Xu et al, 2017). In zebrafish mimicking SPG3, the modulation of the BMP pathway was also of interest to rescue the motor phenotype (Fassier et al, 2010).…”

Section: Therapeutic Options and Opportunitiesmentioning

confidence: 99%

Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

Elsayed

Eltazi

Ahmed

et al. 2021

Front. Mol. Biosci.

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Hereditary spastic paraplegias (HSP) are a heterogeneous group of motor neurodegenerative disorders that have the core clinical presentation of pyramidal syndrome which starts typically in the lower limbs. They can present as pure or complex forms with all classical modes of monogenic inheritance reported. To date, there are more than 100 loci/88 spastic paraplegia genes (SPG) involved in the pathogenesis of HSP. New patterns of inheritance are being increasingly identified in this era of huge advances in genetic and functional studies. A wide range of clinical symptoms and signs are now reported to complicate HSP with increasing overall complexity of the clinical presentations considered as HSP. This is especially true with the emergence of multiple HSP phenotypes that are situated in the borderline zone with other neurogenetic disorders. The genetic diagnostic approaches and the utilized techniques leave a diagnostic gap of 25% in the best studies. In this review, we summarize the known types of HSP with special focus on those in which spasticity is the principal clinical phenotype (“SPGn” designation). We discuss their modes of inheritance, clinical phenotypes, underlying genetics, and molecular pathways, providing some observations about therapeutic opportunities gained from animal models and functional studies. This review may pave the way for more analytic approaches that take into consideration the overall picture of HSP. It will shed light on subtle associations that can explain the occurrence of the disease and allow a better understanding of its observed variations. This should help in the identification of future biomarkers, predictors of disease onset and progression, and treatments for both better functional outcomes and quality of life.

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Section: Therapeutic Options and Opportunitiesmentioning

confidence: 99%

Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

Elsayed

Eltazi

Ahmed

et al. 2021

Front. Mol. Biosci.

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“…In most patients, brain MRI shows white matter lesions around corona radiata, semioval center and lateral ventricles. The “ears of the lynx” imaging sign suggests the presence of a genetic mutation, likely characteristic of HSP ( 12 ). The narrowing of corpus callosum is another relevant imaging characteristic in these patients.…”

Section: Discussionmentioning

confidence: 99%

Hereditary spastic paraplegia (SPG 48) with deafness and azoospermia: A case report

et al. 2023

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Hereditary spastic paraplegias (HSP) are inherited neurodegenerative disorders characterized by progressive paraplegia and spasticity in the lower limbs. SPG48 represents a rare genotype characterized by mutations in AP5Z1, a gene playing a role in intracellular membrane trafficking. This study describes a case of a 53-year-old male patient with SPG48 presenting spastic paraplegia, infertility, hearing impairment, cognitive abnormalities and peripheral neuropathy. The Sanger sequencing revealed a homozygous deletion in the chr 7:4785904-4786677 region causing a premature stop codon in exon 10. The patient's brother was heterozygous for the mutation. The brain magnetic resonance imaging found a mild brain atrophy and white matter lesions. In the analysis of the auditory thresholds, we found a significant hearing decrease in both ears.

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“…According to an extended analysis of all SPG48 patients by Breza et al (2021), 21 AP5Z1 variants (SPG48) from 18 families have been identified in the literature. 7 Some examples include Slabicki et al (2010) who identified a homozygous truncating mutation in 2 affected French sibs (613653.0001). Another patient with sporadic disease was heterozygous for another truncating mutation (613653.0002).…”

Section: Discussionmentioning

confidence: 99%

First SPG48 case report in India with a novel mutation

Gongati¹,

Agrawal

Agrawal³

2023

IJN

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The hereditary spastic paraplegias (HSP) are a large group of inherited neurologic disorders that share the primary symptom of difficulty in walking due to weakness and spasticity in the lower limbs. Spastic paraplegia-48 (SPG48) is an autosomal recessive neurologic disorder characterized by spasticity of the lower limbs resulting in gait difficulties. Biallelic mutations in AP5Z1 are known to cause this complex form of hereditary spastic paraplegia (HSP) referred to as SPG48 (MIM#613647). Most patients have onset in mid- or late-adulthood, although childhood onset has been reported in 1 patient. Additional features may include parkinsonism, urinary incontinence, neuropathy, and mild cognitive impairment. We report a 49-year-old male with SPG48 with a novel mutation. This is the first SPG48 case report in an Indian patient and to the best of our knowledge this mutation is the first to be reported worldwide.

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Expanding the Spectrum of AP5Z1‐Related Hereditary Spastic Paraplegia (HSP‐SPG48): A Multicenter Study on a Rare Disease

Cited by 9 publications

References 7 publications

Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

Hereditary spastic paraplegia (SPG 48) with deafness and azoospermia: A case report

First SPG48 case report in India with a novel mutation

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