Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), also known as hereditary diffuse leukoencephalopathy with spheroids (HDLS) andpigmentary orthochromatic leukodystrophy (POLD), refers to a rare inherited autosomal dominant disease characterised by an adult-onset leukodystrophy that usually leads to death in around 5-7 years. It is considered to belong to the microgliopathies.

Terminology

For many years hereditary diffuse leukoencephalopathy with spheroids (HDLS)and pigmentary orthochromatic leukodystrophy (POLD) were considered to be two separate hereditary leukoencephalopathies. Sometimes HDLS was also called neuroaxonal leukodystrophy. The striking similarities in clinical presentation and histology suggested a link between the two diseases for a long time and HDLS and POLD are now considered to be part of the same disease spectrum, which researchers have recommended calling adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) ¹.

Epidemiology

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is considered a rare disease, typically manifesting between ages 30 and 50 years. Its exact prevalence is unknown, as it has been previously mistaken for many other diseases and it might thus continue to be underdiagnosed. 

While it is usually an inherited disease, there exist case reports of proven de novo mutations and mutation carriers without clinical symptoms currently up to the age of over 70 years ².

Clinical presentation

Patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) can have a wide variety of symptoms that usually exhibit a rapid progression and lead to death within a couple of years due to progressive motor impairment.

Typical symptoms are:

• depression, which might precede the other symptoms
• neuropsychiatric symptoms, progressing to dementia
• motor impairment, with extrapyramidal and pyramidal symptoms that usually lead to tetraparesis
• apraxia and rarely ataxia
• epilepsy

Pathology

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is caused by autosomal dominantly inherited mutations in the colony-stimulating factor 1 receptor (CSF1R) gene. The mutations can be proven by genetic testing of blood samples. Before the identification of the underlying genetic cause of the disease, a brain biopsy was needed to establish the diagnosis. Neuropathologic findings usually show gliosis, white matter destruction with pigmented glia and/or axonal spheroids and macrophages.

Radiographic features

CT

Small periventricular calcifications, often only seen on thin sagittal reconstructions with a bone kernel are a typical imaging finding. Affected areas show a low attenuation and no contrast enhancement.

MRI

Presymptomatic mutation carriers

Mutation carriers usually show non-specific T2 hyperintense lesions of the white matter that are pronounced for the age of the patient. MR spectroscopy in these lesions is usually normal without characteristic findings.

Symptomatic patients

Characterised by bilateral, asymmetric patchy or confluent areas of subcortical and deep white matter signal change, usually most pronounced in the frontal lobe followed by the parietal lobe with a relative sparing of the temporal lobe. The corticospinal tract is usually affected late in the disease course. Progression leads to a severe atrophy of the supratentorial white matter. The cerebellum and brainstem are usually spared ^3,4.

• T1: affected areas are low in signal
• T1 C+ (Gd): no enhancement is visible
• T2/FLAIR: hyperintense
• DWI: small spots of diffusion restriction, that can be visible over months have been described as a characteristic finding ³
• MR spectroscopy: (in symptomatic patients)
  • reduced N-acetylaspartate (NAA)
  • increased choline
  • increased myo-inositol
  • increased lactate

Treatment and prognosis

Currently, there exists no accepted specific therapy and the disease is inevitably fatal within a couple of years. In a few cases, haematopoietic stem cell transplantation was attempted as an individual cure, leading to clinical stabilisation in some cases but also therapy associated death in one case¹⁰.

Differential diagnosis

The main differential for ALSP is leukoencephalopathy due to autosomal recessive mutations in the mitochondrial alanyl-transfer RNA (tRNA) synthetase gene (AARS2-L), another adult-onset leukodystrophy with similar pathologic findings. The clinical presentation and imaging findings in AARS2-L strongly resemble those of ALSP, but there are subtle differences ^8,9.

General imaging differential considerations include ^2-6:

• multiple sclerosis
• cerebral vasculitis
• CADASIL

Clinical differential considerations include ^2-6:

• Alzheimer disease
• frontotemporal dementia
• atypical parkinsonism