Klinische FragestellungSpastische Paraplegie, autosomal rezessiv; Differentialdiagnose

NGS + x

[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. Autosomal rezessive HSP ist sehr heterogen, auch werden neue Gene identifiziert. Neue Ursachen der autosomal rezessiven HSP können auf eine Familie oder auf ein Einzel-Individuum beschränkt sein. Autosomal rezessive HSP kommt bei ca. 25%-30% aller HSP-Patienten vor. 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], AR
• Allelic: Amyotrophic lateral sclerosis 5, juvenile (SPG11)
• Allelic: Anemia, sideroblastic, 3, pyridoxine-refractory (GLRX5)
• Allelic: Boucher-Neuhauser syndrome (PNPLA6)
• Allelic: Charcot-Marie-Tooth disease, axonal, type 2X (SPG11)
• Allelic: Combined oxidative phosphorylation deficiency 7 (C12orf65)
• Allelic: Congenital anomalies of kidney + urinary tract 1 (DSTYK)
• Allelic: Deafness, AR 119 (AFG2B)
• Allelic: Hyperphenylalaninemia, BH4-deficient, B (GCH1)
• Allelic: Hyperuricemia, pulmonary hypertension, renal failure + alkalosis (SARS2)
• Allelic: Laurence-Moon syndrome (PNPLA6)
• Allelic: Leukodystrophy, hypomyelinating, 2 (GJC2)
• Allelic: Lymphatic malformation 3 (GJC2)
• Allelic: Neurodegeneration with brain iron accumulation 4 (C19orf12)
• Allelic: Oliver-McFarlane syndrome (PNPLA6)
• Allelic: Spinocerebellar ataxia 28 (AFG3L2)
• 3-methylglutaconic aciduria with deafness, encephalopathy + Leigh-like syndrome (SERAC1)
• 3-methylglutaconic aciduria, type III (OPA3)
• Aicardi-Goutieres syndrome 2 (RNASH2B)
• Aicardi-Goutieres syndrome 6 (ADAR)
• Allelic: Parkinson disease 5, susceptibility to (UCHL1)
• Allelic; Spastic paraplegia 79A, AD (UCHL1)
• Argininemia (ARG1)
• Cataracts, spastic paraparesis, speech delay (FAR1)
• Cerebral palsy, spastic quadriplegic, 1 (GAD1)
• Cerebroretinal microangiopathy with calcifications + cysts 2 (STN1)
• Cerebrotendinous xanthomatosis (CYP27A1)
• Charcot-Marie-Tooth disease, axonal, type 2U (MARS1)
• Chediak-Higashi syndrome (LYST)
• Coenzyme Q10 deficiency, primary, 7 (COQ4)
• Dystonia, DOPA-responsive (GCH1)
• Friedreich ataxia (FXN GAA)
• Gastrointestinal defects and immunodeficiency syndrome 2 (PI4KA)
• Glycogen storage disease IV (GBE1)
• Hengel-Maroofian-Schols syndrome (BCAS3)
• Hereditary spastic paraplegia [MONDO:0019064, panelapp] (CCDC82)
• Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome (SLC25A15)
• Hypomyelination with brainstem + spinal cord involvement + leg spasticity (DARS1)
• Krabbe disease (GALC)
• Kufor-Rakeb syndrome (ATP13A2)
• Leukodystrophy, hypomyel., 7, with/-out oligodontia and/or hypogonadotropic hypogonadism (POLR3A)
• Leukodystrophy, hypomyelinating, 13 (HIKESHI)
• Leukodystrophy, hypomyelinating, 21 (POLR3K)
• Leukodystrophy, hypomyelinating, 3 (AIMP1)
• Leukodystrophy, hypomyelinating, 4 (HSPD1)
• Leukodystrophy, progressive, early childhood-onset (ACER3)
• Martsolf syndrome 1 (RAB3GAP2)
• Mast syndrome (SPG21)
• Mental retardation, AR 42 (PGAP1)
• Mitochondrial complex I deficiency, nuclear type 23 (NDUFA12)
• Neurodevelopmental disorder [MONDO:0700092, panelapp] (CCDC82)
• Neurodevelopmental disorder with hearing loss + spasticity (AFG2B)
• Neurodevelopmental disorder with microcephaly + spastic paraplegia (GPT2)
• Neurodevelopmental disorder with neuromuscular + skeletal abnormalities (NRCAM)
• Neurodevelopmental disorder with progressive spasticity + brain white matter abnormalities (HPDL)
• Neurodevelopmental disorder with spastic quadriplegia + brain abnorm. with/-out seizures (WDR45B)
• Neurodevelopmental disorder with spasticity, seizures + brain abnormalities (NSRP1)
• Neurodevelopmental disorder, motor impairment, no language, cerebral hypomyel., brain atr. (TAF8)
• Neuropathy, hereditary motor + sensory, type VIB (SLC25A46)
• Parkinson disease 15, AR (FBXO7)
• Peroxisomal fatty acyl-CoA reductase 1 disorder (FAR1)
• Pituitary adenoma 4, ACTH-secreting, somatic (USP8)
• Polyglucosan body disease, adult form (GBE1)
• Polymicrogyria, perisylvian, with cerebellar hypoplasia + arthrogryposis (PI4KA)
• Pontocerebellar hypoplasia, type 1B (EXOSC3)
• Pontocerebellar hypoplasia, type 1E (SLC25A46)
• Progressive Spastic Paresis [panelapp] (SARS2)
• Severe ID + global developmental delay, epilepsy [panelapp] (BLOC1S1)
• Sjogren-Larsson syndrome (ALDH3A2)
• Spastic ataxia 2, AR (KIF1C)
• Spastic ataxia 3, AR (MARS2)
• Spastic ataxia 4, AR (MTPAP)
• Spastic ataxia 5, AR (AFG3L2)
• Spastic ataxia 8, AR, with hypomyelinating leukodystrophy (NKX6-2)
• Spastic ataxia 9, AR (CHP1)
• Spastic ataxia, Charlevoix-Saguenay type (SACS)
• Spastic paralysis, infantile onset ascending (ALS2)
• Spastic paraplegia + psychomotor retardation with/-out seizures (HACE1)
• Spastic paraplegia 11, AR (SPG11)
• Spastic paraplegia 13, AD (HSPD1)
• Spastic paraplegia 15, AR (ZFYVE26)
• Spastic paraplegia 18, AR (ERLIN2)
• Spastic paraplegia 23 (DSTYK)
• Spastic paraplegia 26, AR (B4GALNT1)
• Spastic paraplegia 28, AR (DDHD1)
• Spastic paraplegia 30, AR (KIF1A)
• Spastic paraplegia 35, AR (FA2H)
• Spastic paraplegia 39, AR (PNPLA6)
• 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 53, AR (VPS37A)
• Spastic paraplegia 54, AR (DDHD2)
• Spastic paraplegia 55, AR (MTRFR syn. C12orf65)
• Spastic paraplegia 56, AR (CYP2U1)
• Spastic paraplegia 57, AR (TFG)
• Spastic paraplegia 5A, AR (CYP7B1)
• Spastic paraplegia 61, AR (ARL6IP1)
• Spastic paraplegia 62, AR (ERLIN1)
• Spastic paraplegia 63, AR (AMPD2)
• Spastic paraplegia 64, AR (ENTPD1)
• Spastic paraplegia 7, AR (SPG7)
• Spastic paraplegia 72, AR (REEP2)
• Spastic paraplegia 74, AR (IBA57)
• Spastic paraplegia 75, AR (MAG)
• Spastic paraplegia 76, AR (CAPN1)
• Spastic paraplegia 77, AR (FARS2)
• Spastic paraplegia 78, AR (ATP13A2)
• Spastic paraplegia 79B, AR (UCHL1)
• Spastic paraplegia 82, AR (PCYT2)
• Spastic paraplegia 83, AR (HPDL)
• Spastic paraplegia 84, AR (PI4KA)
• Spastic paraplegia 86, AR (ABHD16)
• Spastic paraplegia 87, AR (TMEM63C)
• Spastic paraplegia 9B, AR (ALDH18A1)
• Spastic paraplegia, childhood, complicated [genereviews] (KLC4)
• Spastic paraplegia, optic atrophy + neuropathy (KLC2)
• Spastic tetraplegia, thin corpus callosum + progressive microcephaly (SLC1A4)
• Spasticity, childhood-onset, with hyperglycinemia (GLRX5)
• Spinocerebellar ataxia, AR 18 (GRID2)
• Troyer syndrome (SPART)
• Warburg micro syndrome 2 (RAB3GAP2)