Dr. H. Toplak:
The patient under discussion is a 55-year-old woman who was admitted to hospital due to atypical MS and irritable bowel syndrome (IBS). Focusing on the term atypical MS and considering the medical history of the patient, one gets the impression that this diagnosis is more speculative than definitive, although it could point to another diagnosis, such as a metabolic disorder. The notion of IBS is also not very helpful for finding the final diagnosis, because it is a diagnosis of exclusion. Taken together, these are two vague diagnoses that according to the protocol will lead to a final diagnosis on the basis of a simple, noninvasive test.
Although the patient did not report weight loss, malabsorption syndromes have to be considered. Celiac disease was excluded by duodenal biopsy and serology. Whipple’s disease can be excluded because it is associated with progressive weight loss, abdominal pain, lymph node involvement, enteropathic arthritis, spondyloarthropathy, microcytic hypochromic anemia, and further signs and symptoms not observed in this case. Moreover, the neurological symptoms in Whipple’s disease are not transient as described for this patient and the disease is very rare in women.
The patient reported a 15-year history of neurological symptoms, such as transient paresis of the left arm, vertigo and disturbance of equilibrium, transient paresthesia and headaches. The MRI showed slightly progressive white matter lesions over the past 10 years, resulting in the diagnosis of atypical MS. White matter lesions can, however, also occur in systemic diseases, such as systemic lupus erythematosus, scleroderma, Sjögren’s syndrome and idiopathic demyelinating diseases. Since several autoimmunological parameters were negative and CSF analysis did not show oligoclonal bands, i. e. there was no increase of Igs in CSF, an autoimmune disease can most likely be excluded. Laboratory blood and CSF data, however, revealed mild chronic inflammation, probably due to an infection or a reaction to something as yet unknown. Viral infection with Epstein-Barr virus (EBV), CMV and tick-borne viral meningoencephalitis also causes white matter lesions, as does bacterial infection with Borrelia (neuroborreliosis), but serological tests for several viruses and Borrelia were negative. Other tests for evaluation of any viral or bacterial infection could possibly have been invasive and so are ruled out because the final diagnosis was made by performing a simple, noninvasive test.
The information that a therapeutic trial with glucocorticoids for 9 months had a temporary positive effect but administration of interferon-beta 1a did not improve symptoms, is not really helpful for reaching a final diagnosis because we have no details on dosage and definite duration of the therapies. Information about certain neurological symptoms persisting for years, arterial hypertension and physical examination without abnormal abdominal findings except for abdominal discomfort on deep palpation does also not really help to establish a final diagnosis. From all the results so far, only the finding of hypertensive cardiomyopathy (thickness of septum 15 mm) seems to be important for the further differential diagnosis.
Due to the involvement of multiple organ systems with no obvious morphological correlation and the thickened cardiac septum, chronic intoxication could be suspected to cause this woman’s health problems. Chronic lead poisoning can for instance result in MS-like symptoms or cause migraine and fatigue. Chronic exposure to amalgam containing mercury, cadmium and aluminum could also cause such symptoms. Moreover, vasculitis can induce white matter lesions and cause abdominal pain. Side effects of chemotherapy have been reported to be similar to the symptoms seen here, but this can be ruled out due to the negative history. Further diagnoses, such as amyloidosis, chronic fatigue syndrome, hypothyroidism and disturbances of the pituitary/adrenal axis may show some similar symptoms but do not seem to suffice to explain this patient’s problems.
Taken together there are four important features for the establishment of the final diagnosis: (1) probable chronic intoxication with reactive inflammation, (2) a thickened cardiac septum, (3) white matter lesions and (4) IBS.
The family history of the patient was reported to be negative. Actually, it is so unremarkable that it should be checked again in more detail. In daily routine physicians always focus on well-defined diseases with characteristic symptoms. In children with unclear or nonspecific symptoms, genetically determined metabolic diseases are more likely to be considered than in adults. Various metabolic diseases can cause severe symptoms but depending on the genotype may also present with milder symptoms. In individuals with mild genetic defects or in those who are heterozygous, especially X‑linked heterozygous, symptoms are often discrete rather than severe and distinct. Adrenoleucodystrophy (ADL) and adrenomyeloneuropathy (AMN), for example, are X‑linked inherited metabolic diseases due to disturbed peroxisomal degradation of very long chain fatty acids. Depending on the ADL genotype, the phenotype significantly differs depending on the age at which the disease is manifested and the symptoms, which vary from mild to very severe. Keeping this in mind, I would strongly suggest that the discussed patient suffers from a mild form of a certain metabolic disorder.
Considering all the available information, I think that she suffers from a lysosomal storage disease, since these disorders are known to cause the typical neurological symptoms observed in this case [
1]. Absent or deficient activity of lysosomal exoglycohydrolase α‑galactosidase A (α-D-galactoside galactohydrolase, EC 3.2.1.22) [
2,
3] results in progressive accumulation of globotriaosylceramide (Gb
3, GL-3 or ceramidetrihexoside [CTH]) and related glycosphingolipids (galabiosylceramide) within lysosomes [
4] of various cell types including capillary endothelial cells, renal (podocytes, tubular cells, glomerular endothelial, mesangial and interstitial cells), cardiac (cardiomyocytes and fibroblasts) and nerve cells [
5,
6]. Depending on the affected cells and the degree of involvement at different sites, symptoms will vary from patient to patient. Since Gb
3 can be classified as a kind of neurotoxin, it also causes specific neurological symptoms, as seen in the discussed patient. This progressive, X‑linked inherited disorder of the lysosomal glycosphingolipid metabolism was first but independently described in 1898 by Johannes Fabry and William Anderson [
7,
8] and is thus known as Fabry disease or Anderson-Fabry disease. Both physicians observed a specific distribution of angiokeratoma corporis diffusum in their patients that is characteristic for Fabry disease. Since Fabry disease is an X‑linked inherited disease, classically hemizygous males with no residual α‑galactosidase A activity may display all the characteristic neurological, cutaneous (angiokeratoma), renal (proteinuria, kidney failure), cardiovascular (cardiomyopathy, arrhythmia), cochlear-vestibular and cerebrovascular (transient ischemic attacks, strokes) symptoms of the disease, while heterozygous females often have mild symptoms [
6]. In the past, female heterozygotes were erroneously described as “carriers of the defective gene” and thought to be safeguarded against developing signs and symptoms of the disease. However, women inherit one X chromosome from each parent; in each cell, one X chromosome is randomly inactivated while the other one is active and provides the genetic information. According to the Lyon hypothesis, the degree of X inactivation will determine whether females have a favorable or unfavorable phenotype [
1]. This suggests that it is more appropriate to describe Fabry disease with a wide spectrum of manifestations that range from the classical phenotype in males to a seemingly asymptomatic disease course occasionally observed in females, with a variety of clinical presentations in between. Most female heterozygotes develop symptoms due to yet undetermined mechanisms [
9‐
11]. Females often show vital organ involvement including kidneys, heart and brain approximately a decade later than males [
9]. With age, progressive damage to vital organ systems resulting in organ failure develops in both genders [
9]. End-stage renal disease and life-threatening cardiovascular or cerebrovascular complications reduce life expectancy [
12‐
15]. Fabry disease affects multiple organ systems; early signs and symptoms of the disease are summarized in Table
1. Neurological symptoms are present in almost every patient, cutaneous and renal symptoms are seen in every second patient. Half of the patients also show the characteristic cornea verticillata [
16] that rarely affects vision but is readily detectable by slit lamp examination, i. e. “a simple, noninvasive examination that led to the final diagnosis” as stated in the protocol. Posterior subcapsular spoke-like cataracts and retinal vessel tortuosity are also seen [
17].
Table 1
Early signs and symptoms of Fabry disease [
6]
Nervous system | Acroparesthesia |
Nerve deafness |
Heat intolerance |
Hearing loss, tinnitus |
Gastrointestinal tract | Nausea, vomiting, diarrhea, postprandial bloating and pain, early satiety |
Difficulty gaining weight |
Skin | Angiokeratomas |
Hypohidrosis |
Eyes | Corneal and lenticular opacities |
Vasculopathy (retina, conjunctiva) |
Kidneys | Microalbuminuria, proteinuria, impaired concentration, hyperfiltration, increased urinary Gb3 excretion |
Heart | Heart rate variability, arrhythmias, abnormal electrocardiogram (shortened PR interval), mild valvular insufficiency |
Cardiac symptoms, such as left ventricular hypertrophy, arrhythmia, angina and dyspnea are reported in about 40–60% of patients with Fabry disease [
14,
18‐
21]. These patients often have left ventricular abnormalities. The septum thickness in particular can show significant alterations since the posterior wall may become thinner with age due to fibrosis; concentric hypertrophy has been reported as the most common structural change [
18] and was also seen in our patient. The cardiomyopathy in Fabry disease is characterized by reduced myocardial contraction and relaxation. Right ventricular hypertrophy with normal chamber size and preserved systolic but impaired diastolic function reflects the typical right ventricular structural and functional changes in this disease [
6]. Right ventricular wall thickness, age and left ventricular mass index are significantly correlated in Fabry disease [
22] and there is a relationship between the degree of right ventricular involvement and the left ventricular cardiomyopathy stage [
23].
Gastrointestinal symptoms have been reported in 50–70% of patients with Fabry disease [
12,
13] and frequently include diarrhea and abdominal pain [
24]. These symptoms may be due to the deposition of Gb
3 in the enteric ganglia and mesenteric blood vessels [
25]. Many patients have an alternating pattern of diarrhea, normal stool or constipation. This clinical manifestation is reminiscent of IBS, as are symptoms of abdominal discomfort and bloating associated with food intake [
26]. Patients with Fabry disease tend to be diagnosed with diarrhea-predominant IBS [
27].