Table 5.
Fifty-six ‘red flag’ clinical, laboratory, and radiologic characteristics raising suspicion for Mendelian diseases in patients evaluated for multiple sclerosis or with ‘multiple sclerosis-like’ phenotypes
| Disease characteristic | Red Flaga | Examples of alternative inherited disorders |
|---|---|---|
| Clinical neurologic or neuro-ophthalmologic features | ||
| Peripheral neuropathy/delayed NCV | Major | CMTX, KD, MLD, X-ALD/AMN, cblC defect, PLP1 disease, CTX, mito disease, POLG, APBD |
| Myopathy | Major | Mito disease, POLG |
| Amyotrophy | Major | Specific HSP subtypes |
| Retinopathy | Major | Mito disease, cblC defect |
| Prominent cerebrovascular disease | Major | CADASIL, FD |
| Prominent neuropsychiatric disease/dementia | Intermediate | MLD, WD, HDLS, CTX, cblC defect |
| Isolated, progressive or intermittent ataxia | Intermediate | FA, spinocerebellar ataxia, CTX, PDH deficiency |
| Apparently isolated myelopathy | Minor | X-ALD/AMN, cblC defect |
| Early, severe optic nerve involvement | NA | LHON, X-ALD, OPA1 disease, CLCN2 disease |
| Prominent dystonia/parkinsonism | NA | NPC, CHD, MLC1 disease, CTX, NBIA, WD, APBD, Leigh disease and other mito disease |
| Prominent bulbar symptoms | NA | AOAD, KD |
| Prominent epilepsy | NA | MLD, cblC defect, POLG, MELAS/MERFF, other mito disease |
| Palatal myoclonus | NA | AOAD |
| Hearing loss | NA | FD, NPC, Leigh disease, other mito disease |
| Vertical supranuclear gaze palsy (VSGP) | NA | NPC |
| Gelastic cataplexy | NA | NPC |
| Tongue hemiatrophy | NA | KD |
| Relapsing-remitting neurological symptoms or stroke-like episodes | NA | PDH deficiency, MELAS/MERFF, CMTX; cblC defect, MTHFR deficiency, CADASIL, FD |
| Gender discrepancy in clinical neurological phenotype or more severely affected brothers/male maternal relatives (implying X-linked disease) | NA | FD, X-ALD/AMN, PLP1 disease/SPG2; CMTX, PDH deficiency |
| Extra-neurologic features | ||
| Renal disease | Major | FD, MMA |
| Cutaneous angiokeratomas | Major | FD |
| Liver disease | NA | UCD, mito disease, POLG, NPC, WD |
| Cardiomyopathy | NA | FD, mito disease |
| Tendon xanthomas | NA | CTX |
| Early cataract/lenticular opacity | NA | FD, WD, CTX |
| Symptomatic anaemia | NA | WD, MMA/cobalaminopathies |
| Adrenocortical insufficiency | NA | X-ALD/AMN |
| Recurrent abdominal pain | NA | AIP, FMF, FD |
| Chronic diarrhoea | NA | CTX, mito disease |
| Laboratory findings | ||
| Elevated lactate, plasma | Major | mtDNA disorders, POLG, PDH deficiency; MMA |
| Elevated CK, plasma | NA | Mito disease, POLG |
| Elevated mean corpuscular volume | NA | MMA/cobalaminopathies |
| Haemolytic anaemia | NA | WD |
| Persistently elevated methylmalonic acid, plasma/urine (with normal B12) | NA | MMA/cobalaminopathies |
| Hyperhomocysteinaemia and/or homocystinuria | NA | cblC defect; MTHFR deficiency |
| Neuroimaging appearances | ||
| Pattern/distribution of white matter involvement | ||
| Frontal (anterior) predominance | NA | MLD, HDLS, ADLD |
| Parieto-occipital (posterior) predominance | NA | X-ALD, KD, CTX |
| Periventricular predominance | NA | APBD |
| Symmetric, confluent white matter abnormalities | Intermediate | MLD, SPG11, CMTX, other leukodystrophies and leukoencephalopathies |
| Anterior temporal lobe, external capsule | NA | CADASIL/CARASIL |
| Sparing of the U-fibres | NA | MLD, CXT, APBD, Krabbe |
| Early involvement of U-fibres | NA | MTHFR deficiency, mito disease, APBD |
| Sparing of the corpus callosum | NA | APBD, MLC1 disease |
| Corticospinal/pyramidal tract involvement | NA | KD, HDLS, X-ALD/AMN, mito disease |
| Other findings | ||
| Cerebellar/brainstem signal abnormality | NA | AMN, CTX, AOAD, ADLD, POLG, APBD |
| Gadolinium contrast enhancement | NA | X-ALD/AMN, POLG, AOAD |
| T2 hyperintensities of dentate nucleus | Major | CTX, WD, mito disease |
| T1 hyperintensities of pulvinar | Major | FD |
| Symmetric T2 hyperintensity of basal ganglia | Major | Leigh disease, other mito disease; CTX |
| Calcification on CT | Intermediate | Mito disease |
| Elevated white matter lactate on MRS | Intermediate | Mito disease, LBSL, X-ALD |
| Cystic change or degeneration of white matter | NA | PLP1 disease/SPG2, CLC2, mito disease |
| ‘Eye of the tiger’ appearance to GP | NA | NBIA |
| Prominent brainstem/upper cord atrophy | NA | AOAD |
| Prominent cerebellar atrophy | NA | CHD, NPC, spinocerebellar ataxia |
| Cord hyperintensity | NA | cblC defect, MTHFR deficiency, CTX, mito disease, B12/folate deficiencies, AOAD, LHON |
aMajor, intermediate, and minor red flags as determined by Miller et al., 2008 (NA, not addressed).
ADLD = autosomal dominant leukodystrophy; AIP = acute intermittent porphyria; AMN = adrenomyeloneuropathy; AOAD = adult-onset Alexander disease; APBD = adult polyglucosan body disease; cblC = cobalamin C defect; CARASIL = cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; CHD = Chédiak-Higashi disease; CK = creatine kinase; CLC2 = CLC2 disease; CMTX = X-linked Charcot–Marie–Tooth disease; CTX = cerebrotendinous xanthomatosis; FD = Fabry disease; FMF = familial Mediterranean fever; GP = globus pallidus; HDLS = hereditary diffuse leukoencephalopathy with spheroids; KD = Krabbe disease; LBSL = leukoencephalopathy with brain stem involvement and lactate elevation; MLD = metachromatic leukodystrophy; MMA = methylmalonic acadaemia; MRS = magnetic resonance spectroscopy; MTHFR = methylenetetrahydrofolate reductase; NBIA = neurodegeneration with brain iron accumulation; NCV = nerve conduction velocity; NPC = Niemann-Pick disease type C; PDH = pyruvate dehydrogenase deficiency; POLG = polymerase gamma-related disease; UCD = urea cycle disorders; X-ALD = X-linked adrenoleukodystrophy.