Alpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder caused by mutations in the MAN2B1 gene. ^{Reference Riise Stensland, Frantzen and Kuokkanen1} To date, a total of 154 variants have been identified in 191 patients worldwide. ^{Reference Riise Stensland, Frantzen and Kuokkanen1} Symptoms usually begin in childhood, but milder forms may present only in adulthood. The most frequent systemic findings include skeletal abnormalities (81%), facial dysmorphia (70%), deafness (67%), immunodeficiency (recurrent respiratory tract infections; 53%), and organomegaly (namely, hepatosplenomegaly; 41%). ^{Reference Zielonka, Garbade, Kölker, Hoffmann and Ries2} Nervous system involvement not only includes intellectual disability (>90%) but also psychomotor developmental regression, behavioral alterations and ataxia. ^{Reference Zielonka, Garbade, Kölker, Hoffmann and Ries2} Brain magnetic resonance imaging (MRI) data is limited, with leukodystrophy and cerebellar atrophy representing the most frequently reported abnormalities. ^{Reference Majovska, Nestrasil and Paulson3} Clinical-imaging descriptions are relevant to prompt recognition of this potentially treatable entity.

Herein is presented the case of a 49-year-old female patient born from healthy consanguineous parents. Birth and perinatal periods were unremarkable and motor and language acquisitions followed normal milestones. At the age of 7, psychomotor regression was noticed after a normal first year at primary school, as well as gait impairment and speech and learning difficulties. Around the same period, hearing loss was also perceived. At the age of 14, the patient presented bilateral tonic−clonic seizures. In subsequent years, the clinical picture was dominated by intellectual disability and the girl was never capable of attending school or working. At the age of 42, she was referred to our Neurology Department for the first time, due to cognitive deterioration, aggressiveness, and frequent falls. Medical history included hepatosplenomegaly, metrorrhagia, and early menopause. Bone abnormalities and past recurrent infections were denied. Neurological examination revealed cognitive delay, poor spontaneous speech, axial, and appendicular choreo-dystonic movements, axial instability, and ataxic gait. Facial dysmorphia was also notorious, comprising low set ears, prognathism, and high forehead. Brain MRI showed symmetrical T2-weighted images hyperintensity of superior aspects of both thalami (Figure 1A, B − arrows) and dentate nuclei (DN) of cerebellum (Figure 1C, D − arrowheads). Periventricular white matter hyperintensity on T2-FLAIR sequence was mild (Figure 1E, F) and no cerebellar atrophy was shown. During the 7 years of follow-up, the patient presented progressive cognitive deterioration, as well as motor and behavioral fluctuations. In 2020, clinical exome analysis identified a novel homozygous variant in MAN2B1 (NM_000528.4:c.1061C>T, p. Ser354Phe), initially classified as having uncertain clinical significance. Biochemical studies subsequently established a causal association by showing reduced alpha-mannosidase enzymatic activity in total peripheral blood leukocytes (1 nmol/h/mg protein; reference value 77−413) and abnormal urinary levels of mannose-rich oligosaccharides. In view of these findings, the new MAN2B1 variant was reclassified as likely pathogenic.

This study reports a childhood-onset case evaluated in adulthood of alpha-mannosidosis exhibiting rare neurological features (epilepsy and choreo-dystonic movements) and a novel MAN2B1 variant. Additionally, thalami and DN hyperintensity here described have not been previously reported, including in one series of 13 patients. ^{Reference Zielonka, Garbade, Kölker, Hoffmann and Ries2} Previous brain MRI descriptions of alpha-mannosidosis comprised cerebellar and cortical atrophies, leukodystrophy, basal ganglia and thalami T2 hypointensity, corpus callosum thinning, Virchow−Robin spaces and widened perioptic cerebrospinal fluid spaces. ^{Reference Majovska, Nestrasil and Paulson3–Reference Zoons, de Koning, Abeling and Tijssen5} In recent quantitative studies, Majovska et al. did not confirm basal ganglia and thalami T2 hypointensity, suggesting that T2 hypointensity seen in these locations is due to adjacent white matter T2 hyperintensity and not to gray matter iron deposition, as formerly believed. ^{Reference Majovska, Nestrasil and Paulson3,Reference Zoons, de Koning, Abeling and Tijssen5} The range of differential diagnoses of thalami and DN hyperintensity in neuropediatric genetic/metabolic disorders is narrow and includes cerebrotendinous xanthomatosis, Canavan disease, L2-hydroxyglutaric, and type 1 glutaric acidurias, Alexander´s disease, Leigh syndrome, and Wilson disease. ^{Reference Van Cauter, Severino and Ammendola6–Reference Hegde, Mohan, Lath and Lim8} We additionally propose that alpha-mannosidosis, traditionally regarded as a white matter disease, should be considered in the approach to central gray matter (thalami and DN) hyperintensity.

Figure 1:

T2-weighted images performed at 49 years of age, showing symmetrical hyperintensity of superior aspects of both thalami (A, B – arrows) and dentate nuclei of cerebellum (C, D – arrowheads). Periventricular white matter hyperintensity on T2-FLAIR sequence was mild (E, F).