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Autosomal Recessive Spastic Paraplegia Type 56

SPG56


Presentation

  • Each entry follows a 5 section structure that will cover (1) essential features of the disorder (2) physiological basis of the disorder (3) neuropsychological and other clinical presentation (4) assessment and diagnostic practices (5) evidence-based treatments[books.google.com]
  • Autosomal recessive spastic paraplegia type 18 (SPG18) is a rare, complex type of HSP that presents in early childhood.[cags.org.ae]
  • Muscle weakness when present is seen in iliopsoas, tibialis anterior and, to a lesser extent, the hamstrings.[jnnp.bmj.com]
  • Asymptomatic patients are also present.[emedicine.medscape.com]
  • The sister carrying the R294H variant had an ataxic gait and hand tremor at 3 years, which was not present in her sister.[epilepsygenetics.net]
Weakness
  • See also: Leg: Leg weakness, leg sensations, leg paresthesias, leg tingling, leg numbness Knee: knee weakness, knee sensations, knee paresthesias, knee tingling, knee numbness Foot: foot weakness, foot sensations, foot paresthesias, foot tingling, foot[familydiagnosis.com]
  • Although the disorder is typically referred to as hereditary spastic paraplegia the degree of weakness is variable and ranges from no weakness (full strength) to marked weakness (paraplegia).[rarediseases.org]
  • Abstract Hereditary spastic paraplegia (HSP) is a neurological disorder characterized by a progressive spasticity and muscle weakness of the lower limbs. It is divided into two subtypes, uncomplicated and complicated forms.[nature.com]
  • They also had symptoms of pseudobulbar palsy including increased jaw and glabellar reflexes and weak cough sound. They had mild-moderate distal pyramidal weakness, with only a flicker of movement at the fingers and forearms noted.[cags.org.ae]
  • HSP is mainly characterized by different degrees of stiffness and weakness of the person's leg muscles and hip muscles, along with gait difficulties and issues with walking.[disabled-world.com]
Disability
  • Accompanying clinical features include intellectual disability, dystonia, cerebellar ataxia, subclinical peripheral neuropathy, visual impairment, as well as abnormalities in brain magnetic resonance imaging.[nature.com]
  • For a subset of patients (n 65), disability was evaluated using the SPATAX-EUROSPA disability score, ranging from 0 (no disability) to 7 (severe disability/confined to bed).[ng.neurology.org]
  • It is characterized by progressive spastic paraplegia associated with delayed motor development, severe intellectual disability and joint contractures. There is no treatment that can prevent or reverse nerve degeneration in HSP.[cags.org.ae]
  • On the pediatric side, genetics is driven by neurodevelopmental disorders (including autism, intellectual disability, and epilepsy) and genetics of rare recessive disorders.[epilepsygenetics.net]
  • Some cases are seriously disabling while others are less disabling and are compatible with a productive and full life.[en.wikipedia.org]
Italian
  • Pigmentary degenerative maculopathy as prominent phenotype in an Italian SPG56/CYP2U1 family . J. Neurol. 263 , 781–783 (2016). 7. Masciullo, M. , Tessa, A. , Perazza, S. , Santorelli, F. M. , Perna, A. & Silvestri, G.[nature.com]
  • (PMID: 28083596) Dhers L … Mansuy D (Cellular and molecular life sciences : CMLS 2017) 3 60 Pigmentary degenerative maculopathy as prominent phenotype in an Italian SPG56/CYP2U1 family.[genecards.org]
  • Italian Journal of Neurological Sciences 11: 583–588.[els.net]
  • Clinical and genetic findings in a series of Italian children with pure hereditary spastic paraplegia. Eur J Neurol 2011; 18:150-157. 6. Arnoldi A, Crimella C, Tenderini E, et al.[1pdf.net]
  • HSPB1 and HSPB8 in inherited neuropathies: study of an Italian cohort of dHMN and CMT2 patients.[ncbi.nlm.nih.gov]
Muscle Weakness
  • Abstract Hereditary spastic paraplegia (HSP) is a neurological disorder characterized by a progressive spasticity and muscle weakness of the lower limbs. It is divided into two subtypes, uncomplicated and complicated forms.[nature.com]
  • Type II was defined as having late onset (older than 35 years), with rapidly developing symptoms and muscle weakness that was more prominent than spasticity.[medlink.com]
  • Like all hereditary spastic paraplegias, spastic paraplegia type 4 involves spasticity of the leg muscles and muscle weakness.[ghr.nlm.nih.gov]
  • Nonetheless, not all patients reach an apparent “leveling off” or functional plateau but instead experience continuous worsening of walking ability due to very slowly progressive muscle weakness and tightness .[rarediseases.org]
Muscle Spasticity
  • One caveat however: although early childhood-onset forms of HSP may be “non-progressive”, the degree of spasticity may increase slowly if adequate range-of-motion is not maintained through stretching exercises and muscle spasticity reduction.[rarediseases.org]
  • To date, treatment of HSPs is primarily directed symptomatically towards reducing muscle spasticity.[els.net]
  • Treatment for HSP is presently limited to symptomatic reduction of muscle spasticity, reduction in urinary urgency, and strength and gait improvement through physical therapy.[link.springer.com]
Visual Impairment
  • Accompanying clinical features include intellectual disability, dystonia, cerebellar ataxia, subclinical peripheral neuropathy, visual impairment, as well as abnormalities in brain magnetic resonance imaging.[nature.com]
  • Additional features include cerebellar ataxia, peripheral neuropathy, amyotrophy, extrapyramidal symptoms, cognitive impairment, deafness and visual impairment [1].[journals.plos.org]
Ectopia Lentis
  • lentis and megalocornea Greenberg dysplasia Griscelli disease type 1 Griscelli disease type 3 Hamel cerebro-palato-cardiac syndrome Hereditary hypercarotenemia and vitamin A deficiency Hereditary proximal myopathy with early respiratory failure Hypocalcemic[csbg.cnb.csic.es]
Spastic Paraplegia
  • Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms . Acta Neuropathol. 126 , 307–328 (2013). 2. Depienne, C. , Stevanin, G. , Brice, A. & Durr, A. Hereditary spastic paraplegias: an update . Curr. Opin.[nature.com]
  • […] rs397514514 Pathogenic, Spastic paraplegia 56, autosomal recessive (SPG56) [MIM:615030] 107,947,388( ) TCATG(A/G)AGAAA intron-variant, reference, missense rs397514515 Pathogenic, Spastic paraplegia 56, autosomal recessive (SPG56) [MIM:615030] 107,945,263[genecards.org]
  • Company Science NGS Panel – Genetic Testing for Spastic Paraplegia Hereditary Spastic Paraplegia (HSP), Spastic paraplegia, SPG, Familial Spastic Paraplegia, Hereditary Spastic Paraparesis, Strumpell-Lorrain Syndrome Hereditary Spastic Paraplegia (HSP[centogene.com]
  • Spastic paraplegia type 7 is part of a group of genetic disorders known as hereditary spastic paraplegias.[ghr.nlm.nih.gov]
Ataxia
  • Metabolic ataxias: The subgroup of metabolic ataxias includes disorders characterized by progressive ataxia, recurrent ataxia and ataxia as a minor feature.[wjgnet.com]
  • Autosomal recessive cerebellar ataxia with oculomotor apraxia (ataxia-telangiectasia-like syndrome) is linked to chromosome 9q34. Am J Hum Genet. 2000 ; 67 : 1320 – 6. 23.[cambridge.org]
  • Friedreich ataxia was the most frequent AR-HCA, followed by ataxia with oculomotor apraxia or ataxia-telangiectasia.[karger.com]
  • Syndromes 87 Spastic Ataxia , Recessive Leukoencephalopathy Macular corneal dystrophy, Congenital cataracts & Myopia : Autosomal Marinesco-Sjögren : SIL1; 5q31 Mental retardation & Epilepsy : WWOX; 16q23 3-Methylglutaconic aciduria, Type III : OPA3;[neuromuscular.wustl.edu]
  • Accompanying clinical features include intellectual disability, dystonia, cerebellar ataxia, subclinical peripheral neuropathy, visual impairment, as well as abnormalities in brain magnetic resonance imaging.[nature.com]
Peripheral Neuropathy
  • Accompanying clinical features include intellectual disability, dystonia, cerebellar ataxia, subclinical peripheral neuropathy, visual impairment, as well as abnormalities in brain magnetic resonance imaging.[nature.com]
  • neuropathy Seizure disorders Todd’s paralysis Neuromuscular disease ALS Anterior cerebral artery occlusion Epidural abscess Stroke Transient ischemic attacks ( TIA ) (“ mini-strokes ”) Migraine Peripheral neuropathy Diabetic peripheral neuropathy Progressive[familydiagnosis.com]
  • Complicated forms are recognized by additional variable features including spastic quadriparesis, seizures, dementia, amyotrophy, extrapyramidal disturbance, cerebral or cerebellar atrophy, optic atrophy, and peripheral neuropathy, as well as by extra[malacards.org]
  • Five patients (2 from family I, 2 from family II, and 1 from family IV) had a peripheral neuropathy diagnosed by neurography and electromyography consisting of axonal motor neuropathy.[ajnr.org]
Cerebellar Ataxia
  • Accompanying clinical features include intellectual disability, dystonia, cerebellar ataxia, subclinical peripheral neuropathy, visual impairment, as well as abnormalities in brain magnetic resonance imaging.[nature.com]
  • Autosomal dominant cerebellar ataxia Autosomal dominant is the manner in which this condition is inherited Types ADCS type1, ADCA type 2, ADCA type 3 Burk, K (1996).[en.wikipedia.org]
  • INTRODUCTION Autosomal recessive cerebellar ataxias (ARCA) constitute a subgroup of the hereditary cerebellar ataxias[ 1 ].[wjgnet.com]
  • Palau F, Espinós C: Autosomal recessive cerebellar ataxias. Orphanet J Rare Dis 2006;1:47. le Ber I, Brice A, Dürr A: New autosomal recessive cerebellar ataxias with oculomotor apraxia. Curr Neurol Neurosci Rep 2005;5: 411-417.[karger.com]
  • HSP due to LYST mutation We encountered an autosomal-recessive (AR) HSP family with cerebellar ataxia and neuropathy whose gene locus was not linked to previously reported AR-HSP loci.[intechopen.com]
Dystonia
  • CYP2U1 mutations in two Iranian patients with activity induced dystonia, motor regression and spastic paraplegia . Eur. J. Paediatr. Neurol. 20 , 782–787 (2016). 9.[nature.com]
  • Recessive Epidemiology: Most Caucasian; 10 patients Clinical Onset age: 8 months to 7 years Extrapyramidal Dystonia Rigidity Choreoathetosis Cerebellum: Ataxia; Nystagmus Spasticity Mental development Poor speech Mental deficiency: Mild to Severe Other[neuromuscular.wustl.edu]
  • Congenital fiber-type disproportion myopathy Ataxia-telangiectasia Ataxia-telangiectasia variant Combined cervical dystonia SHORT syndrome Intellectual deficit, X-linked, Turner type Anhidrotic ectodermal dysplasia - immunodeficiency - osteopetrosis[csbg.cnb.csic.es]
  • The Differential Diagnosis of HSP includes: • Amyotrophic Lateral Sclerosis (ALS) • Tropical spastic paraplegia (caused by HTLV1 infection) • Structural abnormalities of the brain or spinal cord • Dopa-responsive dystonia • Adrenomyeloneuropathy and other[1pdf.net]
  • […] beta-glucosidase glucosidase, beta (bile acid) 2 glucosidase, beta, acid 2 glucosylceramidase, nonlysosomal spastic paraplegia 46 (autosomal recessive) GBA2 SPG46 609471 18986 glutamate decarboxylase 1 0 GAD1 GAD 605363 4092 GTP cyclohydrolase 1 dopa-responsive dystonia[ukgtn.nhs.uk]

Workup

  • Diagnostic workup may be complicated, as SOX10 mutations can present in a mosaic state, with a mild clinical manifestation. SOURCE: Neurol Genet. 2017 May 15;3(3):e151 . doi: 10.1212/NXG.0000000000000151. eCollection 2017 Jun.[hspersunite.org.au]
  • Our findings confirm that this is indeed not an uncommon presentation of this disorder and we suggest that SPG7 gene analysis should be included in the diagnostic workup of autosomal recessive PEO, especially if spasticity is present.[journals.plos.org]

Treatment

  • […] disorders across the lifespan (pediatric, adult, and geriatric populations) Includes interventions and methods of treatment for the outcomes patients may experience[books.google.com]
  • For people with HSP who experience bladder control issues, treatment with oxybutynin might help to relieve bladder spasticity.[disabled-world.com]
  • Treatment [ edit ] No specific treatment is known that would prevent, slow, or reverse HSP. Available therapies mainly consist of symptomatic medical management and promoting physical and emotional well-being.[en.wikipedia.org]
  • Gene Tests for HSP As genes are discovered and assays are developed, Athena Diagnostics brings you additional tests to detect genetic forms of HSP, rule out other significant causes of spastic paraplegia including ALS and guide optimal treatment for the[1pdf.net]
  • There is no treatment that can prevent or reverse nerve degeneration in HSP. Oman Al-Yahyaee et al. (2006) described two families diagnosed with autosomal recessive hereditary spastic paraplegia.[cags.org.ae]

Prognosis

  • Prognosis: predicting symptoms and course of HSP As noted above, there is significant variation in HSP symptoms and their severity. This limits the certainty of making predictions.[rarediseases.org]
  • Prognosis [ edit ] Although HSP is a progressive condition, the prognosis for individuals with HSP varies greatly. It primarily affects the legs although there can be some upperbody involvement in some individuals.[en.wikipedia.org]
  • This distinction is important for genetic counseling of family members and for the patient’s prognosis, in that HSP generally carries a more favorable prognosis. [2] Other components of the differential diagnosis of HSP are similar to those of PLS.[emedicine.medscape.com]
  • Disorders, the prognosis of which differs significantly from HSP, such as multiple sclerosis and familial motor neuron disease should also be excluded. The necessity for investigations will vary depending on the individual clinical picture.[jnnp.bmj.com]
  • […] inversely correlated with quality of life in a previous study. 31 As the majority of patients in our cohort who met the clinical criteria for HSP did not have a genetic diagnosis, this illustrates the need for studies of clinical parameters which influence prognosis[ng.neurology.org]

Etiology

  • Risch N et al. (1999) A genomic screen of autism: evidence for a multilocus etiology. [ ] 26.[moldiag.com]
  • Primary lateral sclerosis The etiology of primary lateral sclerosis (PLS) is unknown, but it may be similar to that proposed for ALS.[emedicine.medscape.com]
  • Etiological heterogeneity in X-linked spastic paraplegia. Am J Hum Genet 1987 ; 41 : 933 –43 Goldblatt J, Ballo R, Sachs B, et al. X-linked spastic paraplegia: evidence for homogeneity with a variable phenotype.[ajnr.org]
  • Through the past 15 years, significant progress has been made in improving our understanding of the genetic etiology of the ARCA.[wjgnet.com]
  • MtDNA defects of either primary or secondary etiology are known to segregate predominantly in clinically affected tissues.[journals.plos.org]

Epidemiology

  • Recessive Epidemiology: Most Caucasian; 10 patients Clinical Onset age: 8 months to 7 years Extrapyramidal Dystonia Rigidity Choreoathetosis Cerebellum: Ataxia; Nystagmus Spasticity Mental development Poor speech Mental deficiency: Mild to Severe Other[neuromuscular.wustl.edu]
  • Consequently, they are often approached together in epidemiological studies.[karger.com]
  • Relevant External Links for CYP2U1 Genetic Association Database (GAD) CYP2U1 Human Genome Epidemiology (HuGE) Navigator CYP2U1 Atlas of Genetics and Cytogenetics in Oncology and Haematology: CYP2U1 No data available for Genatlas for CYP2U1 Gene CYP2U1[genecards.org]
  • Genetic epidemiology of autosomal recessive spastic ataxia of Charlevoix-Saguenay in northeastern Quebec. Genet Epidemiol. 1993 ; 10 : 17 – 25. 27. Hara, K, Onodera, O, Endo, M, Kondo, H, Shiota, H, Miki, K, et al.[cambridge.org]
  • Jorde LB et al. (1990) The UCLA-University of Utah epidemiologic survey of autism: genealogical analysis of familial aggregation. [ ] 6. Abramson RK et al. (1989) Elevated blood serotonin in autistic probands and their first-degree relatives. [ ] 7.[moldiag.com]
Sex distribution
Age distribution

Pathophysiology

  • Pathophysiology [ edit ] The major feature of HSP is a length dependent axonal degeneration. [21] These include the crossed and uncrossed corticospinal tracts to the legs and fasciculus gracilis.[en.wikipedia.org]
  • Koenig[ 10 ] proposed a classification of ARCA based on topographical and pathophysiological criteria, while in the next year the group of Filla proposed a pathogenic classification of the hereditary ataxias[ 11 ].[wjgnet.com]

Prevention

  • There is no treatment that can prevent or reverse nerve degeneration in HSP. Oman Al-Yahyaee et al. (2006) described two families diagnosed with autosomal recessive hereditary spastic paraplegia.[cags.org.ae]
  • Treatment [ edit ] No specific treatment is known that would prevent, slow, or reverse HSP. Available therapies mainly consist of symptomatic medical management and promoting physical and emotional well-being.[en.wikipedia.org]
  • Even though physical therapy does not either prevent or reduce degenerative changes to the person's spinal cord, it is believed that receiving regular therapy can play an important part in assisting people with HSP to maintain and increase their muscle[disabled-world.com]
  • Advances in genetic research in the last decades have improved their diagnosis and brought new possibilities for prevention and future treatments. Still, there is great uncertainty regarding their global epidemiology.[karger.com]

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