Leukodystrophy in Tanzania: A Case Study Highlighting Diagnostic Dilemmas and Clinical Implications

ABSTRACT

Leukodystrophies are rare inherited neurodegenerative disorders characterized by progressive white matter dysfunction and neurological decline. In low‐resource settings, limited access to advanced neuroimaging, biochemical investigations, and genetic testing often delays diagnosis and complicates differentiation from more common infectious, nutritional, and hematological conditions. We describe a 16‐month‐old boy who presented with lower limb weakness, irritability, feeding difficulties, and skin abnormalities during an acute respiratory infection. Initial evaluation raised differential diagnoses including tuberculosis, lymphoma, and leukemia because of overlapping clinical and laboratory features. Neuroimaging demonstrated bilateral periventricular white matter abnormalities and frontotemporal atrophy suggestive of leukodystrophy, with the clinical and radiologic presentation being compatible with suspected metachromatic leukodystrophy (MLD). Subsequent exome sequencing identified a variant in the fructose‐1,6‐bisphosphatase 2 (FBP2) gene associated with childhood‐onset leukodystrophy. However, definitive biochemical and molecular confirmation for MLD, including ARSA enzyme activity, urinary sulfatide analysis, and ARSA/PSAP sequencing, was not available. The patient showed partial clinical improvement following supportive management, including treatment for intercurrent infection and vitamin D deficiency. This case highlights the diagnostic challenges of suspected leukodystrophies in under‐resourced environments, where clinical suspicion often exceeds available diagnostic capacity. Furthermore, it underscores the global disparity in access to specialized metabolic and genetic testing, emphasizing the need for improved multidisciplinary collaboration and expanded diagnostic infrastructure to support timely diagnosis, counseling, and management of rare neurological disorders.

Key Clinical Message

This case highlights the diagnostic challenges of suspected leukodystrophies in resource‐limited settings, where limited access to neuroimaging, metabolic investigations, and genetic testing may delay diagnosis. Early multidisciplinary evaluation is essential for accurate diagnosis, appropriate counseling, and long‐term management of children with progressive neurodegenerative disorders.

1. Introduction

Metachromatic leukodystrophy (MLD) is a rare and devastating inherited metabolic disorder that primarily affects the nervous system [1]. This disorder falls under the category of lysosomal storage diseases and is characterized by the accumulation of lipids called sulfatides within the brain, peripheral nerves, and other tissues [2]. The accumulation of sulfatides leads to the progressive destruction of the white matter in the central nervous system, resulting in severe neurological deficits [3]. MLD is considered a rare disease [3], but its exact prevalence is challenging to determine, especially in low‐resource settings where comprehensive healthcare data may be limited [4]. Globally, the reported incidence of MLD varies, with estimates ranging from 1 in 40,000 to 1 in 160,000 live births [5]. However, underdiagnosis is likely in low‐resource settings due to limited access to specialized diagnostic testing.

MLD can present in different forms, including late‐infantile, juvenile, and adult‐onset forms. The clinical presentation often depends on the age of onset and the specific genetic mutations involved. In the context of low‐resource settings, late‐infantile MLD is of particular concern due to its early onset and rapid progression [6].

Late‐infantile MLD is the most common and severe form of MLD. It typically manifests between 1 and 2 years of age [7], with progressive motor regression, hypotonia, feeding difficulties, dystonia, and loss of developmental milestones. Children with late‐infantile MLD may initially appear healthy but then experience a sudden regression in motor and cognitive skills [8].

Diagnosing MLD can be a complex and resource‐intensive process, involving a combination of clinical evaluation, neuroimaging, and genetic testing [9]. In low‐resource settings, limited access to neuroimaging, ARSA enzyme assays, urinary sulfatide testing, and genetic sequencing can lead to diagnostic uncertainty and delayed recognition. Moreover, the rarity of MLD means that healthcare professionals in such settings may have limited familiarity with the disease, further contributing to diagnostic challenges.

Currently, there is no cure for MLD [10]. Treatment strategies primarily focus on symptom management, supportive care, and optimizing the quality of life for affected individuals. In low‐resource settings, the absence of disease‐modifying therapies further emphasizes the importance of early recognition and appropriate supportive management.

2. Case History and Examination

We present the case of a male child born at term without reported perinatal complications and who initially achieved normal developmental milestones. At 16 months of age, he developed an acute respiratory illness characterized by fever, vomiting, cough, watery diarrhea, and loss of appetite. During the course of the illness, he experienced progressive lower limb weakness with subsequent loss of previously attained motor abilities.

On presentation, he appeared ill, irritable, and dehydrated. Physical examination revealed periorbital edema with discharge, hyperpigmented skin patches over the abdomen, and neurofibroma‐like lesions on the left forearm and neck. Neurological examination demonstrated minimal spontaneous motor activity, generalized lower extremity dystonia, and severe feeding difficulties requiring nasogastric tube feeding for 8 weeks. There was no reported family history of genetic disorders, neurological disease, or chronic illnesses.

The child had previously received anti‐tuberculosis treatment at a peripheral health facility, although no documentation of diagnostic confirmation or treatment follow‐up was available. At presentation, there were no clinical features suggestive of active tuberculosis.

3. Differential Diagnosis, Investigations and Treatment

Based on the clinical presentation of developmental regression, motor impairment, and systemic symptoms, the initial differential diagnoses included tuberculosis, leukemia, and lymphoma. Additional differential diagnoses considered for progressive neurodegenerative disorders included leukodystrophies, inherited metabolic disorders, cerebral palsy variants, mitochondrial disorders, and other causes of developmental regression (Table 1).

TABLE 1.

Differential diagnosis of leukodystrophies and related disorders considered in comparison with the index patient.

Disorder	Typical clinical features	Neuroimaging features	Diagnostic testing	Comparison with index patient
Metachromatic leukodystrophy (MLD)	Progressive motor regression, hypotonia/spasticity, gait disturbance, feeding difficulties, cognitive decline; late infantile form most common	Symmetrical periventricular white matter changes with cerebral atrophy	ARSA enzyme assay, urinary sulfatides, ARSA/PSAP genetic testing	The patient demonstrated motor regression, dystonia, feeding difficulties, and bilateral periventricular white matter abnormalities compatible with suspected MLD; however, confirmatory biochemical and molecular testing was unavailable
Remitting childhood‐onset leukodystrophy associated with FBP2 variant	Episodic developmental regression, weakness, hypotonia, encephalopathy often triggered by infection or metabolic stress	Variable white matter abnormalities; may improve over time	Exome sequencing identifying FBP2 variants	An FBP2 variant was identified in our patient, and symptom onset followed an acute infectious illness with partial clinical improvement during follow‐up
Krabbe disease	Irritability, developmental regression, hypertonia/spasticity, seizures, feeding difficulties	Diffuse demyelination involving corticospinal tracts and cerebellum	Galactocerebrosidase enzyme assay, GALC gene testing	Considered due to developmental regression and feeding difficulties, although imaging findings were less characteristic
X‐linked adrenoleukodystrophy (X‐ALD)	Progressive neurological decline, behavioral changes, adrenal insufficiency, spasticity	Posterior predominant white matter lesions	Very long‐chain fatty acid assay, ABCD1 gene testing	Less likely due to absence of adrenal manifestations and imaging pattern not suggestive of X‐ALD
Canavan disease	Developmental delay, hypotonia progressing to spasticity, macrocephaly	Diffuse white matter involvement with spongiform degeneration	Elevated N‐acetylaspartate levels, ASPA gene testing	Macrocephaly and characteristic metabolic findings were absent
Pelizaeus–Merzbacher disease	Nystagmus, hypotonia, developmental delay, ataxia, progressive spasticity	Hypomyelination on MRI	PLP1 gene testing	Clinical course and imaging were not typical for hypomyelinating disorders
Mitochondrial/Metabolic encephalopathies	Developmental regression, hypotonia, seizures, episodic deterioration during illness	Variable basal ganglia and white matter abnormalities	Metabolic screening, mitochondrial genetic testing	Considered because symptom onset followed systemic illness and included multisystem manifestations
Infectious or nutritional mimics (e.g., tuberculosis, vitamin deficiencies)	Fever, weight loss, weakness, developmental delay	Non‐specific imaging findings	Microbiological and nutritional investigations	Initially considered because of recurrent fevers, systemic symptoms, and resource‐limited diagnostic setting

Source: Adapted from Bonkowsky et al. [11] with integration of findings from the present case.

Initial laboratory investigations revealed low serum creatinine (32 μmol/L), elevated blood urea nitrogen (8.65 mmol/L), hypokalemia (3.41 mmol/L), and normal alkaline phosphatase levels. Radiographic evaluation of the left lower limb demonstrated a supracondylar fracture of the left femur. Following clinical deterioration characterized by recurrent high‐grade fever, vomiting, and loose stools on the seventh day of admission, further investigations were performed. Complete blood count showed leukocytosis with a white blood cell count of 12.47 × 10⁹/L.

A brain computed tomography (CT) scan demonstrated symmetrical hypodensities in the periventricular white matter of the frontal and parietal lobes bilaterally, together with frontotemporal atrophy. These findings were suggestive of leukodystrophy and clinically compatible with suspected metachromatic leukodystrophy (MLD). Genetic testing using whole‐exome sequencing identified a variant in the fructose‐1,6‐bisphosphatase 2 (FBP2) gene, previously associated with remitting childhood‐onset leukodystrophy (OMIM #619864). However, confirmatory investigations for MLD, including arylsulfatase A (ARSA) enzyme activity testing, urinary sulfatide analysis, and ARSA/PSAP gene sequencing, were unavailable at our institution.

The patient was managed with rehydration therapy, electrolyte correction, nutritional support, and symptomatic treatment, resulting in improvement of dehydration and diarrhea. Orthopedic management of the femoral fracture involved immobilization with a hip spica cast for 6 weeks. Following recurrence of fever and gastrointestinal symptoms during hospitalization, empiric antibiotic therapy was initiated for suspected intercurrent infection. Cholecalciferol supplementation was prescribed for documented vitamin D deficiency. During hospitalization, the patient showed gradual clinical improvement, with increased spontaneous motor activity and stabilization of his general condition. Follow‐up radiographs demonstrated satisfactory healing and remodeling of the femoral fracture. After discharge, the child attended neuro‐pediatric and occupational therapy clinics; however, subsequent long‐term follow‐up information was unavailable as the patient was later lost to follow‐up.

4. Conclusion and Results (Outcome and Follow‐Up)

The patient demonstrated gradual clinical improvement following supportive management, including rehydration therapy, nutritional support, antibiotic treatment for suspected intercurrent infection, vitamin D supplementation, and orthopedic management of a left femoral supracondylar fracture. Over a 3‐month follow‐up period, feeding ability improved, and partial recovery of motor function was observed. Follow‐up radiographs confirmed satisfactory healing and remodeling of the femoral fracture. However, significant neurodevelopmental deficits persisted, particularly in speech and language function, as the child remained unable to speak coherently at 30 months of age.

Neuroimaging findings were suggestive of leukodystrophy, and genetic testing identified a variant in the FBP2 gene associated with remitting childhood‐onset leukodystrophy. Although definitive confirmation of metachromatic leukodystrophy (MLD) was not possible because ARSA enzyme activity testing, urinary sulfatide analysis, and ARSA/PSAP sequencing were unavailable, the clinical presentation, radiological findings, and genetic results supported the diagnosis of an inherited white matter disorder.

This case highlights the diagnostic challenges posed by leukodystrophies in resource‐limited settings, where access to specialized biochemical and genetic investigations remains limited. Early recognition of developmental regression and characteristic neuroimaging findings is essential to facilitate timely diagnosis, supportive care, rehabilitation, and family counseling. Strengthening access to advanced diagnostic services and multidisciplinary care pathways may improve the evaluation and management of children with rare neurogenetic disorders in low‐resource settings. Unfortunately, the patient was lost to follow‐up after 3 months, limiting assessment of long‐term neurological outcomes.

5. Discussion

In this case report, we describe a child with suspected childhood‐onset leukodystrophy associated with an FBP2 gene variant, whose clinical and radiological features were compatible with metachromatic leukodystrophy (MLD) among other inherited white matter disorders. However, definitive biochemical and molecular confirmation of MLD was not possible because specialized investigations, including ARSA enzyme activity testing and ARSA/PSAP sequencing, were unavailable. To our knowledge, this represents one of the first reported cases of a genetically characterized suspected leukodystrophy from Tanzania.

In low‐ and middle‐income countries (LMICs), particularly in sub‐Saharan Africa, the burden of neurological disorders continues to rise and contributes substantially to long‐term disability and mortality. Patients with suspected neurogenetic conditions in Tanzania frequently encounter major barriers to diagnosis and care, including limited specialist services, low public awareness, financial constraints, and restricted access to diagnostic investigations. Recurrent misdiagnoses and poor understanding of these disorders often lead families to seek help from traditional or faith healers, while stigma and misconceptions within communities may further isolate affected individuals. Consequently, many patients remain undiagnosed or untreated, and only a small proportion are eventually assessed by neurologists or multidisciplinary teams. In addition to the neurological burden itself, affected patients and families commonly experience psychological distress, social exclusion, and reduced educational and employment opportunities [12].

MLD is a rare and devastating neurodegenerative disorder with distinct challenges, particularly in low‐resource settings [13]. This case exemplifies the complexity of diagnosing suspected MLD and related leukodystrophies in such environments, where limited access to specialized healthcare services and diagnostic tools can lead to delayed or missed diagnoses [1]. Late‐infantile MLD is characterized by rapid regression of motor and cognitive skills, emphasizing the importance of early diagnosis and intervention [14].

The clinical manifestations and degree of neurodegeneration in metachromatic leukodystrophy (MLD) are highly variable and are influenced by the underlying genetic mutation and the severity of enzyme deficiency. Disease onset and phenotype may differ significantly even among siblings carrying the same mutation, suggesting that additional biochemical, environmental, or epigenetic factors may contribute to clinical variability. The late‐infantile form is the most common subtype, accounting for approximately 50%–60% of reported cases [15]. Diagnosis of MLD typically relies on a combination of clinical assessment, neuroimaging, genetic analysis of the ARSA and PSAP genes, and biochemical evaluation of ARSA enzyme activity in leukocytes, skin fibroblasts, or urine samples. Prenatal diagnosis may also be performed through analysis of ARSA activity and sulfatide accumulation in amniotic fluid cells to distinguish true disease from ARSA pseudo deficiency. However, such investigations remain challenging in low‐resource settings because of limited availability and high cost. In our setting, magnetic resonance imaging (MRI) was unavailable at the time of presentation, and the patient's family could not afford additional specialized diagnostic investigations [15].

Diagnostic hurdles in low‐resource settings are exacerbated by the rarity of MLD and limited familiarity among healthcare professionals. This often results in delayed diagnoses, hindering timely therapeutic interventions. Genetic testing, while essential for confirmation, may not be readily available or affordable in these settings [10]. In our case, the absence of ARSA enzyme activity testing and urinary sulfatide analysis limited definitive confirmation of MLD.

There is no curative treatment for MLD, although disease‐modifying therapies such as gene therapy, enzyme replacement therapy, and hematopoietic stem cell transplantation are under investigation [15, 16]. However, these interventions remain largely inaccessible in low‐resource settings, necessitating reliance on supportive and symptomatic care. In the index case, this limitation was compounded by financial constraints.

The implementation of genetic testing for neurological disorders in Tanzania remains at an early stage, with only limited availability in selected specialist or research centers. Comprehensive molecular diagnostics are costly and remain inaccessible to many patients, making precise genetic diagnoses uncommon in routine clinical practice. Although certain genetic investigations such as newborn screening and paternity testing are available, broader testing for inherited neurological conditions is not yet widely established. In our case, advanced genetic analysis was only possible through international collaborative initiatives, with exome sequencing kindly performed free of charge in the Netherlands. This further highlights the significant disparity between clinical suspicion and access to confirmatory diagnostic testing in resource‐limited settings [12].

The identification of an FBP2 variant underscores the genetic heterogeneity and phenotypic overlap seen among leukodystrophies [15]. Although FBP2 variants have been associated with remitting childhood‐onset leukodystrophy rather than classical ARSA‐related metachromatic leukodystrophy (MLD), the clinical and radiologic features observed in our patient remained compatible with suspected MLD and other inherited white matter disorders. This case highlights the diagnostic uncertainty frequently encountered in resource‐limited settings, where advanced biochemical and molecular investigations are often unavailable. Further research is needed to better define the phenotypic spectrum and genetic diversity of leukodystrophies across different populations [16].

In low‐resource settings, management is further complicated by limited access to multidisciplinary care, neurorehabilitation services, and specialized diagnostic testing. This case emphasizes the importance of maintaining a broad differential diagnosis and exercising caution when assigning definitive diagnostic labels in the absence of confirmatory investigations. Resource‐appropriate strategies focusing on symptomatic management, nutritional support, rehabilitation, and caregiver education remain central to patient care.

Author Contributions

William Nkenguye: conceptualization, data curation, investigation, methodology, writing – original draft, writing – review and editing. Mujaheed Suleman: conceptualization, data curation, investigation, writing – original draft, writing – review and editing. Jay Lodhia: conceptualization, investigation, resources, supervision, validation, writing – original draft, writing – review and editing.

Funding

The authors have nothing to report.

Ethics Statement

Ethical approval was obtained from the Department of Pediatrics and Kilimanjaro Christian Medical Centre Ethical Board on 02/01/2025 Ref KCMC/D.GS/A.01/015.

Consent

Written informed consent was obtained from the patient's parents/legal guardian for publication and any accompanying images. A copy of the written consent is available for review by the Editor‐in‐Chief of this journal on request.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

deidentiified data will be available upon request.