In adulthood, spinal cord MRI abnormalities such as T2-weighted hyperintensities and atrophy are commonly associated with a large variety of causes (inflammation, infections, neoplasms, vascular and spondylotic diseases). Occasionally, they can be due to rare metabolic or genetic diseases, in which the spinal cord involvement can be a prominent or even predominant feature, or a secondary one. This review focuses on these rare diseases and associated spinal cord abnormalities, which can provide important but over-ridden clues for the diagnosis. The review was based on a PubMed search (search terms: ‘spinal cord’ AND ‘leukoencephalopathy’ OR ‘leukodystrophy’; ‘spinal cord’ AND ‘vitamin’), further integrated according to the authors’ personal experience and knowledge. The genetic and metabolic diseases of adulthood causing spinal cord signal alterations were identified and classified into four groups: (1) leukodystrophies; (2) deficiency-related metabolic diseases; (3) genetic and acquired toxic/metabolic causes; and (4) mitochondrial diseases. A number of genetic and metabolic diseases of adulthood causing spinal cord atrophy without signal alterations were also identified. Finally, a classification based on spinal MRI findings is presented, as well as indications about the diagnostic work-up and differential diagnosis. Some of these diseases are potentially treatable (especially if promptly recognised), while others are inherited as autosomal dominant trait. Therefore, a timely diagnosis is needed for a timely therapy and genetic counselling. In addition, spinal cord may be the main site of pathology in many of these diseases, suggesting a tempting role for spinal cord abnormalities as surrogate MRI biomarkers.
- hereditary spastic paraplegia
- metabolic disease
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Adult-onset genetic and metabolic diseases often present with clinical signs of spinal cord involvement, such as spasticity, weakness, sensory ataxia, impairment of vibration and position sensation, and sphincter disturbances.1 In these diseases, MRI of the spinal cord is usually reported as unremarkable, but there can also be varying degrees of spinal white matter abnormalities or at least non-specific spinal cord atrophy.
Excellent reviews describe the features of brain involvement in genetic and metabolic diseases,2–4 but none of them are specifically focused on spinal cord abnormalities.
Moreover, as spinal signal abnormalities are more often found in acquired diseases such as inflammatory, demyelinating, infectious, neoplastic, vascular or spondylotic degenerative diseases, it is very important to identify those cases in which a genetic or metabolic disease should be suspected in order for the clinicians to include these conditions in the differential diagnosis.
This review mainly focuses on the genetic and metabolic causes of spinal cord signal abnormalities in adults. Additionally, we briefly discuss the more frequent finding of non-specific spinal cord atrophy and how to evaluate it.
We performed a PubMed search under the terms ‘leukodystrophy’ AND ‘spinal cord’ (162 papers: 1987–February 2018), ‘leukoencephalopathy’ AND ‘spinal cord’ (223 papers: 1987–February 2018), or ‘vitamin’ AND ‘spinal cord’ (1123 papers: 1987–February 2018). These articles were reviewed by two of the authors (CM and ES) in order to search for all the possible genetic and metabolic causes of spinal cord signal alterations in adult patients. The results of this search have been further integrated according to the personal experience and knowledge of the four authors. The possible genetic and metabolic diseases causing white matter spinal cord signal alterations in adults are aetiologically classified into four groups: (1) leukodystrophies; (2) deficiency-related metabolic diseases (vitamins and minerals); (3) genetic and acquired toxic/metabolic causes; and (4) mitochondrial diseases (table 1). Further, a group of genetic and metabolic disorders causing spinal cord atrophy without signal alterations were also described. A tentative classification based on the spinal MRI findings is also presented (table 2): (1) selective white matter hyperintensities of the dorsal columns±lateral columns; (2) hyperintensities not involving a selective spinal tract; (3) presence of gadolinium enhancement; and (4) spinal cord atrophy without signal alterations. Regarding MRI, in this review we focused mainly on the description of the spinal involvement, whereas the corresponding cerebral findings are reported in table 2.
Genetic and metabolic causes of medullary signal alterations in adults
Leukodystrophies with spinal cord T2 hyperintensities
A hyperintense signal on T2-weighted images in the dorsal columns and lateral corticospinal tract of the spinal cord is one of the major features of leukoencephalopathy with brainstem, spinal cord involvement and lactate elevation, due to recessive mutations in the DARS2 gene, which encodes the mitochondrial aspartyl-transfer RNA synthetase protein5 6 (figure 1). The clinical phenotype is more often a complicated spastic paraparesis associated with cerebellar ataxia and sensory dysfunction. Most of the cases have an infantile (2 to <6 years) or juvenile (6 to <12 years) onset,6 but rare adult-onset cases are reported, usually with a milder, slowly progressive disease.7 8 The diagnosis should be suspected on the bases of radiological features and confirmed directly with genetic testing.
Like in DARS2, mutation in the DARS gene, encoding the cytosolic aspartyl-tRNA synthetase protein,9 can lead to an adult-onset disease with dorsal columns and lateral corticospinal tract involvement. The disease, called hypomyelination with brainstem and spinal involvement and leg spasticity, was initially reported in children,9 but an adult patient with subacute-onset spastic paraplegia and partial responsiveness to steroid was described, suggesting that DARS-related disease may mimic an acquired inflammatory disease.10
Spinal cord signal alterations are reported in patients with adult-onset autosomal dominant leucodystrophy with autonomic symptoms due to LMNB1 mutations. In a series of 23 LMNB1-mutated patients with typical cerebral MRI findings, spinal cord atrophy and pathological white matter signal hyperintensities were found in all the 14 patients who underwent spinal MRI, even at an asymptomatic stage of the disease.11 These subjects displayed posterior column hyperintensity on T2-weighted sequences, often associated with a more widespread involvement of the whole cord white matter, probably reflecting loss of myelinated fibres.11
Atrophy and signal intensity changes at the cervicomedullary junction are the most important MRI findings in patients with juvenile and adult-onset Alexander disease; the atrophy and rarely the signal abnormalities can extend down to the upper spinal cord (figure 1).12–14 Diffuse spinal cord atrophy has also been reported.15 Spinal cord T2 hyperintensities can selectively involve the lateral columns,16 or present a diffuse, transverse involvement,12 or be located in the central region of an atrophic spinal cord.13 A swollen cervical spinal cord and cervical gadolinium enhancement have also been described.12
Very rare cases of genetically and biochemically confirmed ‘spinal cerebrotendinous xanthomatosis’, a disease of cholesterol metabolism due to mutation in the CYP27A1 gene, have been reported.17 18 They differ from the classical cases because of adult-onset, relatively benign course, clinical presentation dominated by spinal symptoms (spastic paraplegia, deep sensation alteration and urinary involvement), and paucity or absence of the classical neurological and systemic symptoms, like bilateral cataract, chronic diarrhoea, xanthomas, learning disability, cerebellar ataxia and polyneuropathy. In some of these patients, spinal MRI studies revealed longitudinally extensive posterior and lateral column white matter abnormalities on T2-weighted images.18–20 As cerebrotendinous xanthomatosis is a treatable disease, by the administration of chenodeoxycholic acid, the detection of these atypical adult-onset spinal cases is particularly important to interfere with disease progression.
Finally, spinal cord T2 signal alterations are exceptionally reported in SPG2 disease, due to PLP1 gene mutations,[s1] [s2] in adult polyglucosan body disease (figure 1),[s3] and in one patient with X linked adrenoleucodystrophy.[s4] Additionally, a modest cervical spinal signal alteration was reported in one patient with severe childhood-onset Pelizaeus-Merzbacher-like disease.[s5] A diffuse gadolinium enhancement of the lumbosacral nerve roots and cauda equina could be found in childhood-onset Krabbe disease [s6] and metachromatic leucodystrophy,[s7] whereas in adult-onset patients affected by these diseases no spinal signal alterations are described, although thinning of the spinal cord is possible.[s8] Since spinal cord signal alterations have not been thoroughly investigated in the advanced stages of all leucodystrophies, possible spinal cord signal alterations cannot be ruled out also in other diseases.
Diseases caused by vitamin or mineral deficiency (genetic or acquired)
Metabolic diseases related to vitamin and mineral deficiency are a well-known cause of clinical and radiological signs of spinal cord involvement.
Biotinidase deficiency, a rare autosomal recessive biotin-responsive disease due to secondary biotin deficiency, could cause a demyelinating myelopathy.21 Disease onset is usually before the age of 5 years with a severe presentation associating seizures, hypotonia, ataxia, breathing problems, skin rash, alopecia, hearing loss, optic atrophy and developmental delay.21 However, later onset cases are also reported, with a subacute or chronic clinical presentation mostly characterised by spastic paraparesis and inconstant optic atrophy.22 23 Spinal MRI frequently shows signal alterations with extensive and transverse inflammatory-like T2 hyperintensity and gadolinium enhancement.24 Selective involvement of spinal cord tracts (dorsal columns, anterolateral tracts and anterior columns) has also been reported.22 23 The late-onset cases mimic inflammatory diseases, especially the neuromyelitis optica spectrum disorder; partial steroid responsiveness was also reported, making the proper diagnosis very challenging.23 25 26 Asymptomatic adults with biotinidase deficiency have been described.23 27–29 The diagnosis could be suspected on the basis of clinical symptoms and of the biological profile (organic acid chromatography, acyl-carnitine profile and inconstant lactic acid increase in the cerebrospinal fluid (CSF)), and confirmed by the enzymatic study of the biotinidase activity and molecular analysis. Early diagnosis and supplementation with low doses of oral biotin could prevent symptom appearance or can reverse most of the clinical and neuroradiological features; however, developmental delay, optic atrophy and auditory problems are often irreversible. Biotinidase neonatal screening is available and applied in many but not all developed countries.29
In vitamin E deficiency, patients present mainly with sensory signs due to both a peripheral nervous system and a spinal dorsal column involvement, more often in the absence of any signal alteration. However, a signal alteration in the posterior columns of the cervical spinal cord may be found in some patients with acquired30 or genetic causes of vitamin E deficiency, notably alpha-tocopherol transfer protein deficiency (ATTP gene)1 and abetalipoproteinaemia.31
Acquired B12 32 33 and copper deficiency34 35 are well-known causes of spinal cord signal alteration, mainly associated with a phenotype of subacute combined degeneration; psychiatric symptoms, peripheral nerve involvement and optic atrophy are also reported in both conditions. Spinal cord signal alterations are not constant and reported in a variable percentage (15%–87%) of B12 deficiency cases36 37 and in about 44% of copper deficiency myelopathy.34 Signal alterations involve the posterior columns mainly at the cervical (‘inverted V sign’) (figure 2) and upper thoracic (‘binoculars sign’) level, or more rarely at the entire thoracic level; lateral column involvement is also described, while anterior cord involvement has been rarely reported in cases of B12 deficiency,37 and isolated central cord signal alterations has been reported in copper deficiency myelopathy.34 Cerebral involvement, largely of brainstem and cerebellum, has been reported in isolated cases,38 but it remains remarkably exceptional and should primarily evoke an alternative diagnosis. In rare cases of B12 deficiency, but not in cases of myelopathy due to copper deficiency, cord expansion and a postcontrast enhancement may be observed, making the differentiation with an inflammatory disease more difficult37 (figure 2). In patients with myelopathy due to B12 deficiency, plasmatic B12 is generally, although not constantly, low and accompanied by increased methylmalonic acid and/or homocysteine, which are more sensitive markers of altered intracellular B12 metabolism; haematological abnormalities, such as megaloblastic anaemia and macrocytosis, are also inconstantly present. In patients affected by myelopathy due to copper deficiency, plasma copper is very low and associated with low ceruloplasmin and low cupruria. In these cases, the main haematological findings are anaemia and leucopaenia.39 These patients respond to B12 parenteral or copper oral or parenteral replacement therapy, although recovery can be slow and incomplete in case of irreversible damage.
Folate deficiency could also rarely cause subacute combined degeneration, very similar to the more frequent myelopathy due to B12 deficiency, and responsive to folate treatment.40
Finally, the mechanism of the acquired AIDS-related myelopathy seems not to be directly related to HIV infection, but to alterations in cobalamin-dependent remethylation pathways, in the absence of folate and B12 defects.41
Genetic and acquired metabolic or toxic diseases
Genetic metabolic diseases with hyperhomocysteinaemia (associated or not with methylmalonic acidemia) are a possible cause of myelopathy in adults. In contrast, no myelopathy has been described in genetic metabolic diseases with an isolated methylmalonic acidemia (ie,methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency, cobalamin (cbl) A, cbl B and cbl D-methylmalonic aciduria diseases). Genetic causes of hyperhomocysteinaemia include remethylation defects with isolated hyperhomocysteinaemia (ie,MTHFR deficiency, cobalamin (cbl) D-homocystinuria, cbl E and cbl G diseases),42 diseases with hyperhomocysteinaemia and methylmalonic acidemia (ie,cbl C, combined cbl D, cbl F and cbl J diseases) and cystathionine beta-synthase deficiency.43 Among these diseases, a myelopathic phenotype (characterised by lower limb spasticity and deep sensory alterations variably associated with peripheral neuropathy, cognitive and psychiatric symptoms) has been described in adults with cbl C disease (figure 2),[s9] and more rarely in MTHFR deficiency,[s10] [s11] and cbl G disease.[s12] Extrapyramidal symptoms, megaloblastic anaemia, ocular manifestation (both optic atrophy and retinopathy), haemolytic uraemic syndromeand pulmonary thrombotic microangiopathy are described in patientswith genetic alterations of intracellular B12 metabolism[s13] [s14] and also in cbl E and cbl G,[s15] but not in MTHFR deficiency. Thromboembolic events are more frequently associated with MTHFR deficiency and cystathionine beta-synthase defect. As a rule, the diagnosis of all these entities is evoked in the presence of increased plasma homocysteine (usually >100 μmol/L), normal B12 level, normal or decreased folate, and increased or normal methylmalonic acid, according to the underlying genetic defect. In the presence of myelopathy, spinal MRI can be normal or presenting a diffuse, abnormal, high-signal intensity on T2-weighted sequences involving the posterior columns and pyramidal tracts at the cervical and dorsal levels, suggestive of subacute combined degeneration.
An acquired metabolic myeloneuropathy with a clinical presentation of subacute combined degeneration could be a consequence of medical or recreational exposure to the anaesthetic gas nitrous oxide, mainly in the context of a pre-existing unsuspected B12 deficiency. Patients usually present with subacute ascending sensory and motor symptoms, pseudoathetosis due to proprioceptive deficit,44 and psychiatric troubles.45 Often, both a peripheral and spinal involvement is present. Spinal MRI shows extensive cervical cord signal alterations involving the dorsal columns and lateral corticospinal tracts, sometimes with cord oedema, cord expansion and contrast enhancement, mimicking an acquired inflammatory or neoplastic disease.46 47 These patients more often have decreased B12 levels, associated with increased homocysteinaemia and methylmalonic acid; however, B12 also could be in the normal ranges, notably in cases of patients with nitrous oxide toxicity after recreational use.45 Importantly, there is a good clinical and radiological responsiveness to a B12 treatment, although the regression of clinical symptoms is slow and sometimes incomplete.
Finally, intrathecal methotrexate treatment is a well-known cause of cerebral leucopathy and myelopathy of toxic metabolic origin, mimicking subacute combined degeneration.48 Contrast enhancement was rarely reported.49 In most of the cases, the cord damage seems to be irreversible, even after folate supplementation.48
Mitochondrial diseases, with the exception of DARS2 mutations, are a rare cause of signal alteration of the spinal cord in adult patients and are usually associated with cerebral involvement. As cerebral leucopathy,50 spinal cord involvement is more frequently reported in children than in adult patients affected by mitochondrial diseases.51 52
In adult patients, spinal cord involvement with partial myelitis, associated with bilateral optic atrophy of variable severity, has been very rarely described in OPA1 mutation,53 and, even more exceptionally, in patient with LHON mutations.54 55 Indeed, a ‘multiple sclerosis-like’ phenotype at the cerebral MRI has been more frequently associated with LHON mutations; some OPA1 patients presented focal cerebral hyperintensities reminiscent of an inflammatory disease, most of them have a progressive course, although some relapsing remitting cases have also been reported, and oligoclonal bands could be found in the CSF; however, gadolinium enhancement has never been described.53 The precise relation (simple association or causal relationship) between the presence of the mutation affecting the mitochondria-related genes LHON and OPA1 and the development of an inflammatory ‘multiple sclerosis-like’ phenotype with bilateral optic neuritis is still a matter of discussion.54 [s16] [s17]
Inherited neurological diseases with spinal cord atrophy and no signal alteration
A large variety of inherited neurological diseases are characterised by degeneration of distal corticospinal tracts, posterior column tracts and/or spinal cord grey matter. On microscopic examination, there can be a loss of myelin, oligodendrocytes, astroglia, neuronal cell bodies and axons, and on gross pathology there can be spinal cord atrophy, that is, a reduction in the cross-sectional area of the spinal cord together with the relative widening of the subarachnoid space at the cervical and thoracic levels. On visual MRI assessment, however, there are no signal abnormalities and spinal cord atrophy, and if present can be overlooked even by a trained radiologist’s eye. Moreover, in inherited neurological diseases, there are few in vivo quantitative MRI studies (total cord area measures, diffusion tensor imaging metrics and tractography) which have investigated the extent of atrophy of the spinal cord in its entire length or at specific levels, notably at the cervical levels.56 57 This is despite spinal cord metrics, including measurements of spinal cord atrophy, can disclose relevant information regarding the pathophysiology of the disease, and are potential biomarkers for monitoring disease progression and for assessment of therapeutic efficacy in clinical trials.
Some genetic cerebral leucodystrophies can show spinal cord atrophy, in the absence of spinal signal alterations (figure 3): this is the case of X linked adrenomyeloneuropathy57 58 and adult polyglucosan disease, due to autosomal recessive mutation in the glycogen branching enzyme gene (GBE1).59 Adrenomyeloneuropathy can also cause a myelopathic phenotype (with motor, sensory and sphincter disturbances) in women, but the presence and degree of spinal cord atrophy have not been systematically investigated in symptomatic women. Moreover, varying degrees of spinal cord atrophy have been reported in hereditary spastic paraplegias, including SPG3A, SPG4, SPG5, SPG6, SPG8 and SPG10,56 60 [s18] as well as in Friedreich’s ataxia,[s19] spinocerebellar ataxia type 1 (SCA1),[s20] and type 3 (SCA3),[s21] autosomal recessive spastic ataxia of Charlevoix-Saguenay, and Gerstmann-Straussler-Scheinker disease with a Pro102Leu mutation in the prion protein gene.[s22] Spinal cord atrophy is also a feature of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophies, including Kennedy’s disease.[s23] [s24]
Some of the above-mentioned diseases could rarely present spinal cord signal alteration, such as in the case of Friedreich’s ataxia or ALS.[s25] [s26]
Spinal cord signal alterations are globally a rare finding in adult patients with genetic and metabolic diseases. They are probably more frequent in children, where they are mostly presenting in disorders due to mitochondrial involvement, such as succinate dehydrogenase deficiency,[s27] SURF1 mutations,55 [s28] Kearns-Sayre syndrome,55 LHON,[s29] LYRM7 mutations,[s30] and mutations in genes coding for Iron–sulfur clusters (ISCs)-related proteins, like GLRX5, causing variant non-chetotic hyperglycinaemia [s31] and ISCA2.[s32] However, we cannot exclude that, in the future, a large phenotypic spectrum of adult-onset cases will be recognised for some of the typical childhood-onset diseases.
Conversely, some genetic leucodystrophies with extensive cerebral involvement in children may manifest at an adult age with a predominant spinal cord involvement (clinical and/or radiological) and less prominent cerebral signal alterations, as in the case of Alexander disease, or some rare DARS and DARS2 mutated adult-onset patients. However, spinal cord signal alterations due to genetic diseases are generally not isolated, and concomitant cerebral involvement is quite always present.
In the evaluation of an adult patient with spinal cord white matter involvement, differential diagnosis with acquired diseases is critical. The global paucity of metabolic and genetic causes of spinal cord signal alterations suggests that the presence of an involvement of the spinal white matter is a major point towards an acquired inflammatory, neoplastic or vascular disease, notably if isolated and not associated with even minor cerebral abnormalities. However, some genetic (DARS mutation, biotinidase deficiency) or acquired (B12 deficiency, methotrexate and nitrous oxide toxicity) treatable metabolic diseases can mimic an inflammatory condition; as they are mostly treatable, their diagnosis should never be missed.
In a schematic approach to an adult patient with spinal cord signal alterations in which a classical inflammatory, tumorous, systemic, osteoarticular or vascular cause has been already ruled out, we therefore suggest to always think to a deficiency-related or toxic metabolic origin because they are mostly treatable diseases; if some of the clues orienting towards a genetic disease are present, the patient could be referred to a specialised centre in order to acquire specific metabolic dosages and genetic analysis (table 1).
The possible major clues in favour of a spinal cord signal alteration of genetic or metabolic origin are (1) positive familiar history of a related disease; (2) selective involvement of the posterior or lateral spinal column tracts; (3) phenotypically complex disease associating other clinical features (skin, ophthalmological, cardiac or acoustic alterations), or combining central and peripheral nervous system involvement with suggestive electromyographic alterations; (4) absence of gadolinium enhancement; (5) chronic progressive evolution; and (6) absence of a clear response to treatment like corticosteroids or immunosuppressant.
However, some important exceptions to these general rules need to be mentioned: a selective spinal signal change in the dorsal columns could be found in patients with acquired dorsal root ganglion alteration (ie, cisplatin toxicity and Sjogren syndrome) as a consequence of a dying-back degeneration; gadolinium enhancement has been reported in Alexander disease, B12 deficiency, biotinidase deficiency and nitrous oxide intoxication; relapsing partial transverse myelitis has been rarely described in biotinidase deficiency, and conversely a chronic progressive evolution is typical of some inflammatory conditions, such as primary progressive multiple sclerosis; and a misleading partial response to steroids has been described in DARS mutation or biotinidase deficiency (table 2).
Finally, the presence of a spinal atrophy without signal alteration is a frequent finding in genetic diseases, but could also be found in chronic acquired disease, such as primary progressive multiple sclerosis, more often in the presence of typical cerebral lesions. Although the presence of diffuse and severe spinal atrophy early after the onset of clinical symptoms suggests a genetic condition, this finding could not be used as a discriminative feature between an acquired or genetic disease. Moreover, spinal atrophy is mostly evaluated visually. This implies that both the degree of atrophy (if present) and its progression over a relatively short timeframe are difficult to be appreciated and, if so, cannot be precisely measured. Spinal cord atrophy measurement may provide new surrogate biomarkers for the follow-up of hereditary degenerative diseases primarily involving the spinal cord. Therefore, future MRI studies focused on quantification of spinal cord atrophy should be a promising area for clinical research.
Additional references can be found in online supplementary file 1.
We wish to thank Dr M Charif, Dr C Carra-Dalliere, Dr F Mochel and Dr L Farina for providing and sharing MRI from their patients. We would also like to thank Dr A Sobieh for his help in MRIs.
CM and ES contributed equally.
Contributors CM and ES were responsible for conception of the work, acquisition of data and drafting of the manuscript. CM, ES, LSP and PL gave substantial contributions to the design of the work, analysis and interpretation of data, critical revision of the manuscript for important intellectual content, and approval of the version published. All authors gave agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding Not required.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement There are no additional unpublished data.
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