Introduction
Challenges to a Genetic Diagnosis
Multiple Genes and a Rapidly Increasing Gene List
Type | Gene | Location | Phenotype MIM number | Inheritance | Identified in more than 1 family with HSP (yes or no) | Allelic disorders/alternative gene-phenotype relationships, MIM number |
---|---|---|---|---|---|---|
SPG1 | L1CAM | Xq28 | MASA syndrome, CRASH syndrome, MIM303350 | XLR | Yes | Partial agenesis of the corpus callosum, MIM308840; hydrocephalus due to aqueductal stenosis, hydrocephalus with congenital idiopathic intestinal pseudoobstruction, hydrocephalus with Hirschsprung disease, MIM307000 |
SPG2 | PLP1 | Xq22.2 | MIM312920 | XLR | Yes | Pelizaeus-Merzbacher disease, MIM312080 |
SPG3A | ATL1 | 14q22.1 | MIM182600 | AD | Yes | Hereditary sensory neuropathy type ID, MIM613708 |
SPG4 | SPAST | 2p22.3 | MIM182601 | AD | Yes | |
SPG5A | CYP7B1 | 8q12.3 | MIM270800 | AR | Yes | Congenital bile acid synthesis defect type 3, MIM613812 |
SPG6 | NIPA1 | 15q11.2 | MIM600363 | AD | Yes | |
SPG7 | SPG7 | 16q24.3 | MIM607259 | AR | Yes | |
SPG8 | KIAA0196 (WSHC5) | 8q24.3 | MIM603563 | AD | Yes | Ritscher-Schinzel syndrome 1, MIM220210 |
SPG9A, B | ALDH18A1 | 10q24.1 | MIM601162, MIM616586 | AD | Yes | AD cutis laxa 3, MIM616603; AR cutis laxa type IIIA, MIM219150 |
SPG10 | KIF5A | 12q13.3 | MIM604187 | AD | Yes | Neonatal intractable myoclonus, MIM617235 |
SPG11 | SPG11 | 15q21.1 | MIM604360 | AR | Yes | Juvenile amyotrophic lateral sclerosis 5, MIM602099; axonal Charcot-Marie-Tooth disease type 2X, MIM616668 |
SPG12 | RTN2 | 19q13.32 | MIM604805 | AD | Yes | |
SPG13 | HSPD1 | 2q33.1 | MIM605280 | AD | Yes | Hypomyelinating leukodystrophy 4, MIM612233 |
SPG14 | - | 3q27-q28 | MIM605229 | AR | No | |
SPG15 | ZFYVE26 | 14q24.1 | MIM270700 | AR | Yes | |
SPG16 | - | Xq11.2 | MIM300266 | XLR | No | |
SPG17 | BSCL2 | 11q12.3 | Silver spastic paraplegia syndrome, MIM270685 | AD | Yes | Progressive encephalopathy with or without lipodystrophy, MIM615924; congenital generalised lipodystrophy type 2, MIM269700; distal hereditary motor neuropathy type VA, MIM600794 |
SPG18 | ERLIN2 | 8p11.23 | MIM611225 | AR | Yes | |
SPG19 | - | 9q | MIM607152 | AD | No | |
SPG20 | SPG20 | 13q13.3 | Troyer syndrome, MIM2759002 | AR | Yes | |
SPG21 | SPG21 | 15q22.31 | MAST syndrome, MIM248900 | AR | Yes | |
SPG22 | SLC16A2 | Xq13.2 | Allan-Herndon-Dudley syndrome, MIM300523 | XL | Yes | |
SPG23 | DSTYK | 1q32.1 | MIM270750 | AR | Yes | Congenital anomalies of kidney and urinary tract 1, MIM610805 |
SPG24 | - | 13q14 | MIM607584 | AR | No | |
SPG25 | - | 6q23-q24.1 | MIM608220 | AR | No | |
SPG26 | B4GALNT1 | 12p11.1-q14 | MIM609195 | AR | Yes | |
SPG27 | - | 10q22.1-q24.1 | MIM609041 | AR | No | |
SPG28 | DDHD1 | 14q22.1 | MIM603940 | AR | Yes | |
SPG29 | - | 1p31.1-p21.1 | MIM609727 | AD | No | |
SPG30 | KIF1A | 2q37.3 | MIM610357 | AD, AR | Yes | AD mental retardation type 9, MIM 614255; hereditary sensory neuropathy type IIC, MIM614213 |
SPG31 | REEP1 | 2p11.2 | MIM610250 | AD | Yes | Distal hereditary motor neuronopathy type VB, MIM614751 |
SPG32 | - | 14q12-q21 | MIM611252 | AR | No | |
SPG33 | ZFYVE27 | 10q24.2 | MIM610244 | AD | No | |
SPG34 | - | Xq24-25 | MIM300750 | XLR | No | |
SPG35 | FA2H | 16q23.1 | MIM612319 | AR | Yes | |
SPG36 | - | 12q23-q24 | MIM613096 | AD | No | |
SPG37 | - | 8p21.1-q13.3 | MIM611945 | AD | No | |
SPG38 | - | 4p16-p15 | MIM612335 | AD | No | |
SPG39 | PNPLA6 | 19p13.2 | MIM612020 | AR | Yes | Laurence-Moon syndrome, MIM245800; Boucher-Neuhauser syndrome MIM215470; Oliver-McFarlane syndrome MIM275400 |
SPG40 | - | - | - | AD | No | |
SPG41 | - | 11p14.1-p11.2 | MIM613364 | AD | No | |
SPG42 | SLC33A1 | 3q25.31 | MIM612539 | AD | No | Congenital cataracts, hearing loss, and neurodegeneration, MIM614482 |
SPG43 | C19orf12 | 19p13.11-q12 | MIM615043 | AR | No | Neurodegeneration with brain iron accumulation 4, MIM614298 |
SPG44 | GJC2 | 1q42.13 | MIM613206 | AR | No | Hypomyelinating leukodystrophy 2, MIM608804 |
SPG45 | NT5C2 | 10q24.3–q25.1 | MIM 613162 | AR | Yes | |
SPG46 | GBA2 | 9p13.3 | MIM614409 | AR | Yes | |
SPG47 | AP4B1 | 1p13.2 | MIM614066 | AR | Yes | |
SPG48 | KIAA0415 | 7p22.1 | MIM613647 | AR | Yes | |
SPG49 | TECPR2 | 14q32.31 | MIM615031 | AR | Yes | |
SPG50 | AP4M1 | 7q22.1 | MIM612936 | AR | Yes | |
SPG51 | AP4E1 | 15q21.2 | MIM613744 | AR | Yes | Familial persistent stuttering 1, MIM184450 |
SPG52 | AP4S1 | 14q12 | MIM614067 | AR | Yes | |
SPG53 | VPS37A | 8p22 | MIM614898 | AR | Yes | |
SPG54 | DDHD2 | 8p11.23 | MIM615033 | AR | Yes | |
SPG55 | C12orf65 | 12q24.31 | MIM615035 | AR | Yes | Combined oxidative phosphorylation deficiency 7, MIM613559 |
SPG56 | CYP2U1 | 4q25 | MIM615030 | AR | Yes | Pseudoxanthoma elasticum |
SPG57 | TFG | 3q12.2 | MIM604484 | AR | Yes | Hereditary motor and sensory neuropathy, Okinawa type, MIM604484 |
SPG58 | KIF1C | 17p13.2 | AR spastic ataxia 2, MIM611302 | AR | Yes | |
SPG59 | USP8 | 15q21.2 | - | AR | No | |
SPG60 | WDR48 | 3p22.2 | - | AR | No | |
SPG61 | ARL6IP1 | 16p12.3 | MIM615685 | AR | Yes | |
SPG62 | ERLIN1 | 10q24.31 | MIM615681 | AR | Yes | |
SPG63 | AMPD2 | 1p13.3 | MIM615686 | AR | No | Pontocerebellar hypoplasia type 9, MIM615809 |
SPG64 | ENTPD1 | 10q24.1 | MIM615683 | AR | Yes | |
SPG66 | ARSI | 5q32 | - | AR | No | |
SPG67 | PGAP1 | 2q33.1 | - | AR | No | AR mental retardation 42, MIM615802 |
SPG68 | KLC2 | 11q13.1 | Spastic paraplegia, optic atrophy, and neuropathy, MIM609541 | AR | Yes | |
SPG69 | RAB3GAP2 | 1q41 | - | AR | No | Martsolf syndrome, MIM212720; Warburg micro syndrome 2, MIM614225 |
SPG70 | MARS1 | 12q13.3 | - | AR | No | AD Charcot-Marie-Tooth disease type 2, MIM616280; interstitial lung and liver disease, MIM615486 |
SPG71 | ZFR | 5p13.3 | - | AR | No | |
SPG72 | REEP2 | 5q31 | MIM615625 | AD, AR | Yes | |
SPG73 | CPT1C | 19q13.33 | MIM616282 | AD | Yes | |
SPG74 | IBA57 | 1q42.13 | MIM616451 | AR | No | Multiple mitochondrial dysfunctions syndrome 3, MIM615330 |
SPG75 | MAG | 19q13.12 | MIM616680 | AR | Yes | |
SPG76 | CAPN1 | 11q13.1 | MIM616907 | AR | Yes | |
SPG77 | FARS2 | 6p25.1 | MIM617046 | AR | Yes | Combined oxidative phosphorylation deficiency 14, MIM614946 |
SPG78 | ATP13A2 | 1p36.13 | MIM617225 | AR | Yes | Kufor-Rakeb syndrome, MIM606693 |
SPG79 | UCHL1 | 4p13 | MIM615491 | AR | Yes | ?Parkinson disease 5, susceptibility to, MIM613643 |
SPG80 | UBAP1 | 9p13.3 | MIM618418 | AD | Yes | |
SPG81 | SELENOI | 2p23.3 | MIM618768 | AR | Yes | |
SPG82 | PCYT2 | 17q25.3 | MIM618770 | AR | Yes | |
SPG83 | HPDL | 1p34.1 | MIM619027 | AR | Yes | |
Unassigned | RNF170 | 8p11.21 | AR | Yes | AD sensory ataxia 1, MIM608984 | |
Unassigned | FAR1 | 11p15.3 | AR | Yes | Peroxisomal fatty acyl-CoA reductase 1 disorder, MIM616154 | |
Unassigned | NEFL | 8p21.2 | AR | Yes | Charcot-Marie-Tooth disease, dominant intermediate G, MIM 617882; Charcot-Marie-Tooth disease type 1F, MIM607734; Charcot-Marie-Tooth disease type 2E, MIM607684 | |
Unassigned | VPS13D | 1p36.22-p36.21 | AR | Yes | Spinocerebellar ataxia, autosomal recessive 4, MIM607317 | |
Unassigned | TUBB4A | 19p13.3 | AD | Yes | Dystonia 4, MIM128101; hypomyelinating leukodystrophy 6, MIM612438 | |
Unassigned | VCP | 9p13.3 | AD | Yes | Charcot-Marie-Tooth disease type 2Y, MIM 616687; frontotemporal dementia and/or amyotrophic lateral sclerosis 6, MIM613954; inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1, MIM167320 | |
Unassigned | POLR3A | 10q22.3 | AR | Yes | Hypomyelinating leukodystrophy 7 with or without oligodontia and-or hypogonadotropic hypogonadism, MIM607694; Wiedemann-Rautenstrauch syndrome, MIM264090 |
Overlap with Other Inherited Disorders
Overlap with the Hereditary Cerebellar Ataxias
Overlap with the Inherited Neuropathies
Overlap with Hereditary Amyotrophic Lateral Sclerosis
Overlap with Monogenic Parkinson Disease
HSP Mimics: Other Mendelian Causes and Management Implications
Disorder | Genetic basis | Mode of inheritance | Additional clinical features | Biochemical findings | Treatment | References |
---|---|---|---|---|---|---|
Adrenoleukodystrophy, MIM 300100; adult adrenomyeloneuropathy, MIM 300100 | ABCD1 | XLR | Sphincter disturbances, sexual dysfunction, adrenocortical dysfunction | Elevated very long chain fatty acids | Corticosteroid replacement therapy for adrenal insufficiency | |
Argininemia, MIM 207800 | ARG1 | AR | Dystonia, dementia, peripheral neuropathy, epilepsy | Newborn screening, elevation of plasma arginine concentration | Measures to reduce ammonia, such as protein-restricted diet, branched-chained amino acids supplement and sodium benzoate. | Tsang et al. [63] |
Biotinidase deficiency, MIM 253260 | BTD | AR | Seizures, hypotonia, limb weakness, ataxia, developmental delay, visual impairment, hearing loss, cutaneous abnormalities | Newborn screening or deficient biotinidase enzyme activity in serum/plasma | Treatment with biotin | |
Primary coenzyme Q10 deficiency 8, MIM | COQ7 | AR | Primary coenzyme Q10 (CoQ10) deficiency is usually associated fatal neonatal encephalopathy with hypotonia, multiple-system atrophy-like phenotype, dystonia, spasticity, seizures, intellectual disability, sensorineural hearing loss, steroid-resistant nephrotic syndrome, hypertrophic cardiomyopathy | Reduced levels of CoQ10 in skeletal muscle or reduced activities of complex I+III and II+III of the mitochondrial respiratory chain on frozen muscle homogenates | 2,4-Dihydroxybenzoate bypass treatment, high-dose oral CoQ10 supplementation | |
Cerebrotendinous xanthomatosis, MIM 213700 | CYP27A1 | AR | Cerebellar signs, intellectual impairment, seizures, peripheral neuropathy, cataract, tendon xanthomas | Elevated levels of cholestanol and bile alcohols in serum and urine | Chenodeoxycholic acid | |
DOPA-responsive dystonia, MIM 128230 | GCH1 | AD, AR | Foot dystonia, later development of parkinsonism, diurnal variation in symptoms, dramatic and sustained response to levodopa | Reduced concentrations of total biopterin and total neopterin in the cerebrospinal fluid | Levodopa/decarboxylase inhibitor | Fan et al. [58] |
Methylmalonic aciduria and homocystinuria cblC type MIM 277400 | MMACHC | AR | Cognitive impairment (5/8), spastic dysuria (3/8), personality change and depression (3/8), ataxia (2/8), seizures (2/8), limb numbness (2/8) and developmental delay (2/8). When patients were diagnosed, the mean serum homocysteine level, the methylmalonic acid level in urine, the serum propionylcarnitine (C3) level and the ratios of C3-to-acetylcarnitine (C2) and free carnitine (C0) were all dramatically elevated. Cranial MRIs showed nothing remarkable except mild brain atrophy. | Elevated urine methylmalonic acid and serum homocysteine levels | Intramuscular cobalamin, oral betaine and folate | Wei et al. [59] |
Homocystinuria due to MTHFR deficiency, MIM 236250 | MTHFR | AR | Polyneuropathy, behavioural abnormalities, cognitive impairment, psychosis, seizures, leukoencephalopathy | Severe hyperhomocysteinemia associated with the characteristic amino acid profile | Betaine and vitamins | Lossos et al. [60] |
Phenylketonuria, MIM 261600 | PAH | AR | Cognitive impairment | Serum phenylalanine concentrations | Classic phenylketonuria diet/protein restricted diet | Kasim et al. [69] |
Dystonia 9, MIM 601042; GLUT1 deficiency syndrome 1, MIM 606777; GLUT1 deficiency syndrome 2, MIM 612126; Stomatin-deficient cryohydrocytosis with neurologic defects, MIM 608885 | SLC2A1 | AD | Seizures, delayed neurologic development, acquired microcephaly, intermittent ataxia, paroxysmal exercise-induced dyskinesia, choreo-athetosis, alternating hemiplegia | Cerebrospinal fluid analysis for hypoglycorrhachia | Ketogenic diet | Verrotti et al. [70] |
HSP Mimics: Overlap with Disorders Without Clear Mendelian Inheritance
When Should a Complex Disorder Be Diagnosed as HSP?
HSP Genes with Different Modes of Inheritance
Individuals with Concurrent Independent Genetic Diagnoses
Pseudodominant Inheritance and Intronic Variants
Strategies for a Genetic Diagnosis
Technique | Pros | Cons |
---|---|---|
Targeted sequencing panels | - Less expensive* - Reduce incidental findings | - Gene list may be restrictive, missing unexpected findings or mutations in genes implicated in overlapping phenotypes - Inadequate coverage of CNVs, SVs; MLPA may be required - Inadequate coverage of deep non-coding variants |
Whole-exome sequencing | - Gene panel not restrictive - Less expensive compared to whole-genome sequencing* | - Inadequate coverage of CNVs, SVs; MLPA may be required s- Inadequate coverage of deep non-coding variants - Challenge of incidental findings |
Whole-genome sequencing | - Gene panel not restrictive - Detection of CNVs, SVs (e.g. deletions in SPAST) - Detection of non-coding variants (see example of deep intronic variants reported in SPG7) | - Expensive* - Challenge of processing, storing and analysing large amounts of data - Challenge of incidental findings |