An Elderly Woman With Frequent Falls and Abnormal MRI

An 87-year-old woman presented with a 4-year history of progressive leg weakness with incontinence and frequent falls. She also had nighttime spasms.

The patient’s past history is unremarkable.

She has a son and a nephew who have leg weakness. It was thought the disease was familial. The nephew was initially thought to have Schilder disease.

A previous MRI of the patient was suggestive of multiple sclerosis.

Physical examination revealed normal mentation and cranial nerves. She had moderate weakness in the lower extremities with increased reflexes and Babinski signs were present. She had absent vibration sense in the legs, and diminished position sense in the toes and feet. She had decreased pinprick up to the mid-calf.

What is the Differential Diagnosis?

This patient has evidence of spinal cord dysfunction and an apparent neuropathy. The differential diagnoses are large, including spinal cord mass or compression in a patient with neuropathy which could be caused by diabetes. Pernicious anemia is also a consideration as well as primary progressive MS. Other possibilities include familial spastic paraparesis and copper deficiency. She had no history of headaches to suggest cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) or weakness to suggest a muscular dystrophy which sometimes is accompanied by MRI abnormalities. Human immunodeficiency virus (HIV) and human T-lymphocytic virus (HTLV) type1 should also be a consideration.

What to do Next?

Blood chemistry profile, hemoglobin A1C, and B ₁₂ /folate were normal.

An EMG showed evidence of an axonal neuropathy and mild sensorimotor axonal neuropathy.

An MRI of the head showed diffuse white matter changes without enhancement ( Fig. 49-1 ), and there was spinal cord atrophy.

It was found that the patient had no B ₁₂ deficiency, and the diagnosis of MS was unlikely. We measured very long chain fatty acids (VLCFAs), which were elevated (docosanoic acid, C22:0 was 2200 and 2.50 [normal, 42.9–112.7], tetracosanoic acid, C24:0 was 200 [normal, 35.6–101.6], and hexacosanoic acid, C26:0 was 7.4 [normal, 0.31–0.81] and the ratio of C24/C22 was 3.3 [normal up to 7.6–0.988] and the ratio of C26:0–C22:0 was 1.5 [normal, 0.049–00118]). It was concluded that this patient had increased levels of VLCFAs. Her son was later tested for the ABCD gene and he had a mutation of this gene. The patient declined DNA testing.

Discussion

It was concluded that this patient had adrenoleukodystrophy due to the elevation of very high fatty acids. No DNA testing was done.

Adrenomyeloneuropathy and adrenoleukodystrophy are the most common peroxisomal disorders with an incidence of 1:14, 700 with a different clinical presentation of the same X-linked genetic mutation with little correlation between the mutations and the phenotype. The disorders are characterized by accumulation of saturated VLCFAs in the brain.

The genetic cause is a mutated gene that encodes the ABCD1 protein, which is a member of the ABC-transported family that functions by transporting VLCAs into the peroxisome, where they undergo beta oxidation.

The childhood form with the effects manifests early: children over age 4–8 years have attention deficit disorder, behavioral disorders, progressive cortical blindness, paraparesis, and seizures accompanied by adrenal insufficiency. The pathological findings of the brains in these patients show intense inflammatory demyelination beginning in the occipital lobes. They do not have a neuropathy.

Adrenal myeloneuropathy is a variant presenting in adults with progressive spastic paraparesis with large fiber sensory loss and sphincter disturbances without inflammatory changes affecting the corticospinal tract, dorsal columns, and peripheral nerves. This usually affects males at ages 20s–30s and affects about 50% of the females who start having symptoms during postmenopausal time. There are about500 mutations of the ABCD gene. Approximately 80% of the cases develop adrenal insufficiency.

The pathophysiology consists of the accumulation of cholesterol and VLCFAs in the nervous system. There is also an accumulation of this in the adrenal glands. This accumulation triggers oxidative stress, apoptosis, and inflammation.

The diagnosis of adrenoneuromyelopathy is difficult unless there is a clear family history and/or other causes of myelopathy or myeloneuropathy have been considered and ruled out. These patients are often misdiagnosed with multiple sclerosis and the differential diagnoses include vitamin B ₁₂ and folate deficiencies, copper accumulation, primary lateral sclerosis, HTLV-1, and familial spastic paraparesis. The final diagnosis is made by genetic testing as well as measuring the VLCFAs which show elevation of C26 and increased ratios of C24.0 and C26.0–C22.0. The female carriers could have elevation of VLCAs, but false-negative tests occur. DNA sequencing, obviously, is more important.

The treatment in adults is conservative although those with adrenal insufficiency receive corticosteroids. In the past diets to reduce VLCFAs have been tried including Lorenzo’s oil, about which a movie was made, and this is a combination of 4:1 erucic acid and oleic acid (glyceryl trioleate and glyceryl trierucate). This has not been demonstrated to be beneficial in clinical trials, but there is a suggestion that it will slow the progression.

Childhood screening allows clinicians to treat children early with hemopoietic stem cell therapy and gene therapy.

Summary

An elderly woman who presented with frequent falls had a myelopathy and a neuropathy with diffuse white matter changes on MRI. She had increased VLCFAs, and her son had an ABCD gene mutation. She has been diagnosed as a manifest carrier of adrenomyeloneuropathy.

Important Points

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Whenever there are diffuse white matter changes on the brain MRI, several other disorders should be ruled out including adrenoleukodystrophy, CADASIL, small vessel disease, and some cases of muscular dystrophy prior to assuming the patient has multiple sclerosis.
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Adrenoleukodystrophy manifests as a myelopathy and peripheral neuropathy showing diffuse white matter changes on the MRI. It is X-linked recessive disorder and could manifest in females with a milder phenotype.
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Adrenoleukodystrophy and adrenoneuromyelopathy are disorders caused by the ABCD1 gene mutation which causes the accumulation of VLCFAs in the brain, spinal cord, and adrenal glands. The diagnosis is made by measuring VLCFAs in blood and DNA testing.
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In adults the treatment is symptomatic. Stem cell treatment therapy and gene therapy are promising in children.
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The MRI on these patients may have white matter changes similar to those in MS.