Klinische FragestellungSpastische Paraplegie, infantil; Differentialdiagnose

NGS +

[Sanger]

Hereditäre spastische Paraplegien (HSPs) sind eine heterogene Gruppe monogener neurologischer Erkrankungen, die durch längenabhängige Degeneration des Kortikospinaltrakts und der Hinterstränge hervorgerufen wird und sich mit bilateraler Spastizität der unteren Extremitäten, Hyperreflexie und Plantar-Reaktionen der Streckmuskeln äußert. HSPs können im Säuglings-, Kindes-, Jugend- oder Erwachsenenalter auftreten. Weiterhin können kognitive Beeinträchtigung, Ataxie, Dysarthrie, Neuropathie oder Krampfanfälle in mehr als der Hälfte der Fälle wichtige Zusatzsymptome sein. Es kommen autosomal dominante, autosomal rezessive oder X-gebundene Vererbungsmodi vor, jeweils mit unterschiedlicher Penetranz und ggf. hochvariabler Expressivität, 13-40% der Fälle treten sporadisch auf. Mittels NGS panel Diagnostik wird die diagnostische Ausbeute signifikant gesteigert, wobei die zusätzlichen Ausbeute-Verbesserungen durch „Exome-“ und „whole genome sequencing“ noch nicht klar zu erkennen sind. Ein unauffälliger genetischer Befund bedeutet nach wie vor keinen sicheren Ausschluss der klinischen Verdachtsdiagnose.

Referenz: https://www.ncbi.nlm.nih.gov/books/NBK1509/

https://www.thelancet.com/action/showPdf?pii=S1474-4422%2819%2930235-2

• Alias: Hereditary spastic paraplegia, HSP
• Alias: Spastic paraplegia, SPG
• Allelic: Adrenoleukodystrophy (ABCD1)
• Allelic: Adrenomyeloneuropathy, adult (ABCD1)
• Allelic: Amyotrophic lateral sclerosis 5, juvenile (SPG11)
• Allelic: Amyotrophic lateral sclerosis, susceptibility to, 25 (KIF5A)
• Allelic: Bile acid synthesis defect, congenital, 3 (CYP7B1)
• Allelic: Boucher-Neuhauser syndrome (PNPLA6)
• Allelic: Charcot-Marie-Tooth disease, axonal, type 2X (SPG11)
• Allelic: Combined oxidative phosphorylation deficiency 14 (FARS2)
• Allelic: Corpus callosum, partial agenesis of (L1CAM)
• Allelic: Cutis laxa, AD 3 (ALDH18A1)
• Allelic: Cutis laxa, AR, type IIIA (ALDH18A1)
• Allelic: Dystonia 9 (SLC2A1)
• Allelic: Encephalopathy, progressive, with/-out lipodystrophy (BSCL2)
• Allelic: Epilepsy, idiopathic generalized, susceptibility to, 12 (SLC2A1)
• Allelic: Erythrokeratodermia variabilis et progressiva 3 (GJA1)
• Allelic: GLUT1 deficiency syndrome 1, infantile onset, severe (SLC2A1)
• Allelic: GLUT1 deficiency syndrome 2, childhood onset (SLC2A1)
• Allelic: Hereditary motor + sensory neuropathy, Okinawa type (TFG)
• Allelic: Hydrocephalus due to aqueductal stenosis (L1CAM)
• Allelic: Hydrocephalus with Hirschsprung disease (L1CAM)
• Allelic: Hydrocephalus with congenital idiopathic intestinal pseudoobstruction (L1CAM)
• Allelic: Hypoplastic left heart syndrome 1 (GJA1)
• Allelic: Immunodeficiency 95 (IFIH1)
• Allelic: Kufor-Rakeb syndrome (ATP13A2)
• Allelic: Laurence-Moon syndrome (PNPLA6)
• Allelic: Leukodystrophy, hypomyelinating, 4 (HSPD1)
• Allelic: Lipodystrophy, congenital generalized, type 2 (BSCL2)
• Allelic: Myoclonus, intractable, neonatal (KIF5A)
• Allelic: Neuronopathy, distal hereditary motor, type VB (REEP1)
• Allelic: Neuropathy, distal hereditary motor, type VA (BSCL2)
• Allelic: Neuropathy, hereditary sensory, type ID (ATL1)
• Allelic: Neuropathy, hereditary sensory, type IIC (KIF1A)
• Allelic: Oliver-McFarlane syndrome (PNPLA6)
• Allelic: Optic atrophy 12 (AFG3L2)
• Allelic: Palmoplantar keratoderma with congenital alopecia (GJA1)
• Allelic: Pelizaeus-Merzbacher disease (PLP1)
• Allelic: Ritscher-Schinzel syndrome 1 (WASHC5)
• Allelic: Singleton-Merten syndrome 1 (IFIH1)
• Allelic: Stomatin-deficient cryohydrocytosis with neurologic defects (SLC2A1)
• Allelic: Stuttering, familial persistent, 1 (AP4E1)
• Allelic: Syndactyly, type III (GJA1)
• 3-methylglutaconic aciduria with deafness, encephalopathy + Leigh-like syndrome (SERAC1)
• 3-methylglutaconic aciduria, type III (OPA3)
• Aicardi-Goutieres syndrome 2 (RNASEH2B)
• Aicardi-Goutieres syndrome 6 (ADAR)
• Aicardi-Goutieres syndrome 7 (IFIH1)
• Allan-Herndon-Dudley syndrome (SLC16A2)
• Allelic: Anemia, sideroblastic, 3, pyridoxine-refractory (GLRX5)
• Allelic: Atrioventricular septal defect 3 (GJA1)
• Allelic: Craniometaphyseal dysplasia, AR (GJA1)
• Allelic: Deafness, AR 119 (SPATA5L1)
• Argininemia (ARG1)
• CRASH syndrome (L1CAM)
• Cataracts, spastic paraparesis + speech delay (FAR1)
• Cerebroretinal microangiopathy with calcifications + cysts 2 (STN1)
• Cerebrotendinous xanthomatosis (CYP27A1)
• Charcot-Marie-Tooth disease, axonal, type 2U (MARS syn. MARS1)
• Developmental + epileptic encephalopathy 32 (KCNA2)
• Developmental and epileptic encephalopathy 89 (GAD1)
• Dystonia 4, torsion, AD (TUBB4A)
• Dystonia, DOPA-responsive, with/-out hyperphenylalaninemia (GCH1)
• Friedreich ataxia (FXN_GAA, FXN)
• Friedreich ataxia with retained reflexes (FXN_GAA, FXN)
• Harel-Yoon syndrome (ATAD3A)
• Hengel-Maroofian-Schols syndrome (BCAS3)
• Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome (SLC25A15)
• Hyperphenylalaninemia, BH4-deficient, B (GCH1)
• Hypomyelination with brainstem, spinal cord involvement + leg spasticity (DARS1)
• Ichthyotic keratoderma, spasticity, hypomyelination + dysmorphic facies (ELOVL1)
• Intellectual developmental disorder, XL syndromic, Claes-Jensen type (KDM5C)
• Krabbe disease (GALC)
• Leukodystrophy, hypomyelinating, 13 (HIKESHI)
• Leukodystrophy, hypomyelinating, 3 (AIMP1)
• Leukodystrophy, hypomyelinating, 6 (TUBB4A)
• Leukodystrophy, hypomyelinating, 7, with/-out oligodontia +/- hypogonadotropic hypogonadism (POLR3A)
• MASA syndrome (L1CAM)
• Mitochondrial complex I deficiency, nuclear type 23 (NDUFA12)
• NESCAV syndrome (KIF1A)
• Neurodevelopmental disorder + motor impairment, no language, cerebr. hypomyel., brain atrophy (TAF8)
• Neurodevelopmental disorder with dysmorphic features, spasticity + brain abnormalities (PGAP1)
• Neurodevelopmental disorder with hearing loss + spasticity (SPATA5L1)
• Neurodevelopmental disorder with microcephaly + spastic paraplegia (GPT2)
• Neurodevelopmental disorder with progressive spasticity + brain white matter abnormalities (HPDL)
• Neurodevelopmental disorder with spasticity, seizures, brain abnormalities (NSRP1)
• Neurodevelopmental disorder with/-out variable brain abnormalities (MAPK8IP3)
• Neurodevelopmental disorder, spastic quadriplegia, brain abnormalities with/-out seizures (WDR45B)
• Neuropathy, distal hereditary motor, type VC (BSCL2)
• Oculodentodigital dysplasia (GJA1)
• Oculodentodigital dysplasia, AR (GJA1)
• Optic atrophy 3 with cataract (OPA3)
• Parkinson disease 5, susceptibility to (UCHL1)
• Peroxisomal fatty acyl-CoA reductase 1 disorder (FAR1)
• Pituitary adenoma 4, ACTH-secreting, somatic (USP8)
• Silver spastic paraplegia syndrome (BSCL2)
• Sjogren-Larsson syndrome (ALDH3L2)
• Spastic ataxia 2, AR (KIF1C)
• Spastic ataxia 5, AR (AFG3L2)
• Spastic ataxia 8, AR, with hypomyelinating leukodystrophy (NKX6-2)
• Spastic ataxia, Charlevoix-Saguenay type (SACS)
• Spastic paralysis, infantile onset ascending (ALS2)
• Spastic paraplegia + psychomotor retardation with/-out seizures (HACE1)
• Spastic paraplegia 10, AD (KIF5A)
• Spastic paraplegia 11, AR (SPG11)
• Spastic paraplegia 12, AD (RTN2)
• Spastic paraplegia 13, AD (HSPD1)
• Spastic paraplegia 15, AR (ZFYVE26)
• Spastic paraplegia 18, AR (ERLIN2)
• Spastic paraplegia 2, XL (PLP1)
• Spastic paraplegia 21 AR; Mast syndrome (SPG21)
• Spastic paraplegia 26, AR (B4GALNT1)
• Spastic paraplegia 28, AR (DDHD1)
• Spastic paraplegia 30, AD, AR
• Spastic paraplegia 31, AD (REEP1)
• Spastic paraplegia 35, AR (FA2H)
• Spastic paraplegia 39, AR (PNPLA6)
• Spastic paraplegia 3A, AD (ATL1)
• Spastic paraplegia 4, AD (SPAST)
• Spastic paraplegia 43, AR (C19orf12)
• Spastic paraplegia 44, AR (GJC2)
• Spastic paraplegia 45, AR (NT5C2)
• Spastic paraplegia 46, AR (GBA2)
• Spastic paraplegia 47, AR (AP4B1)
• Spastic paraplegia 48, AR (AP5Z1)
• Spastic paraplegia 49, AR (TECPR2)
• Spastic paraplegia 50, AR (AP4M1)
• Spastic paraplegia 51, AR (AP4E1)
• Spastic paraplegia 52, AR (AP4S1)
• Spastic paraplegia 55, AR (MTRFR)
• Spastic paraplegia 56, AR (CYP2U1))
• Spastic paraplegia 57, AR (TFG)
• Spastic paraplegia 5A, AR (CYP7B1)
• Spastic paraplegia 6, AD (NIPA1)
• Spastic paraplegia 61, AR (ARL6IP1)
• Spastic paraplegia 62 (ERLIN1)
• Spastic paraplegia 63 (AMPD2)
• Spastic paraplegia 64, AR (ENTPD1)
• Spastic paraplegia 7, AR (SPG7)
• Spastic paraplegia 72, AD + AR (REEP2)
• Spastic paraplegia 73, AD (CPT1C)
• Spastic paraplegia 74, AR (IBA57)
• Spastic paraplegia 76, AR (CAPN1)
• Spastic paraplegia 77, AR (FARS2)
• Spastic paraplegia 78, AR (ATP13A2)
• Spastic paraplegia 79, AR (UCHL1)
• Spastic paraplegia 8, AD (WASHC5)
• Spastic paraplegia 80, AD (UBAP1)
• Spastic paraplegia 82, AR (PCYT2)
• Spastic paraplegia 83, AR (HPDL)
• Spastic paraplegia 86, AR (ABHD16A)
• Spastic paraplegia 87, AR (TMEM63C)
• Spastic paraplegia 88, AD (KPNA3)
• Spastic paraplegia 9A, AD (ALDH18A1)
• Spastic paraplegia 9B, AR (ALDH18A1)
• Spastic paraplegia [panelapp] (GJA1)
• Spastic paraplegia, intellectual disability, nystagmus + obesity (KIDINS220)
• Spastic paraplegia, optic atrophy + neuropathy (KLC2)
• Spastic tetraplegia, thin corpus callosum + progressive microcephaly (SLC1A4)
• Spasticity, childhood-onset, with hyperglycinemia (GLRX5)
• Spinal muscular atrophy, lower extremity-predominant, 2A + 2B, AD (BICD2)
• Spinocerebellar ataxia 28 (AFG3L2)
• Spinocerebellar ataxia, AR 18 (GRID2)
• Troyer syndrome, spastic paraplegia with distal muscle wasting (SPART)
• Ventriculomegaly + arthrogryposis (KIDINS220)
• Wiedemann-Rautenstrauch syndrome (POLR3A)