Late‐Onset Beta‐Propeller Protein‐Associated Neurodegeneration: A Case Report

Beta‐propeller protein‐associated neurodegeneration (BPAN) is an X‐linked dominant form of neurodegeneration with brain iron accumulation (NBIA) related to the WDR45 gene. ¹ , ² , ³ In most patients, the disease first manifests during infancy or childhood as a global developmental delay, early‐onset spastic paraplegia, and epilepsy, with later development of parkinsonism, dystonia, and cognitive decline during adolescence or early adulthood. ⁴ , ⁵ , ⁶ Here we report a late‐onset case of BPAN that contributes to the expansion of its clinical phenotype.

Case Report

A 50‐year‐old woman was evaluated because of an impairment in her left arm dexterity. There was no relevant family history. She had an intellectual disability since childhood that impaired her to manage complex tasks and attain normal school performance but without accompanying motor developmental milestones delay or stereotypic hand movements. At the time of evaluation, she was working in a job adapted for mentally disabled people and was able to manage a small amount of money independently.

Four months before the visit, the patient started to progressively lose dexterity in her left hand. Gait impairment appeared a few weeks later, with lateralization to the left and stiffness in her left leg. The patient denied any speech disturbance or decline in her usual cognitive status.

The initial neurological examination (Video 1) showed mild weakness, spasticity, and hyperreflexia in her left arm with concomitant rigidity and bradykinesia. Milder weakness, spasticity, and hyperreflexia in her left leg caused hemiplegic gait. Subtle parkinsonian signs were also found in the right limbs.

VIDEO 1.

Examination at the time of the first evaluation showed mild weakness and spasticity in the left upper limb, with brisker deep tendon reflexes compared to the contralateral side. Similar findings were present in the left lower limb, together with pathological clonus. The rest of the examination showed bradykinesia, and mild positional tremor predominantly in the left upper limb. The impact of these findings can be seen in the patient's hemiplegic gait.

A brain magnetic resonance imaging (MRI) showed a bilateral hypointense signal in the substantia nigra and globus pallidus on T2 sequences (Fig. 1A,B); this signal was more evident on iron‐sensitive sequences and was more prominent in the substantia nigra compared with the globus pallidus (Fig. 1C,D). T1 sequences did not show a “halo sign” (Fig. 2). Other structural lesions were reasonably excluded after comprehensive MRI imaging.

Figure 1.

(A, B) Axial T2‐weighted magnetic resonance imaging (MRI) showing bilateral hypointense signal in the substantia nigra and globus pallidus. (C, D) Axial T2*‐weighted MRI showing bilateral hypointense signal mainly in the substantia nigra but also in the globus pallidus, indicating iron deposits.

Figure 2.

Axial T1‐weighted magnetic resonance imaging showing the substantia nigra as a thin hypointense linear region, without a hyperintense “halo” surrounding it.

Based on the observation of iron deposition and a clinical pallido‐pyramidal syndrome NBIA was suspected. Proband's DNA was sequenced in a custom Next‐Generation Sequencing gene panel including 11 genes related to NBIA in a NextSeq platform (Illumina).

The patient started treatment with levodopa/carbidopa 100/25 mg t.i.d. After 3 months, left arm dexterity and gait had improved, as evidenced by both the patient and during examination (Video 2). Mild dyskinesias appeared during evaluation in both feet when the patient was distracted. During the following months, motor improvement persisted but the patient reported tightness in her left arm and pectoral area, which was managed with 50 UI botulinum toxin injections into her left pectoral and left biceps muscle, with a good clinical response.

VIDEO 2.

Examination 3 months after dopaminergic drugs were initiated showed an improvement in parkinsonian signs and gait. Mild dopamine‐induced dyskinesias could be observed in the left foot when the patient was performing finger tapping.

Finally, genetic testing confirmed a heterozygous variant in the WDR45 gene. The variant consisted of the deletion of two nucleotides [ChrX (GRCh37): g.48932802_48932803del], resulting in a frameshift and a truncated protein, and it was classified as likely pathogenic according to the American College of Medical Genetics and Genomics guidelines. ⁷ Family segregation analysis of the variant was not available as the patient's parents were deceased at the time of evaluation.

Two years after treatment was initiated, the patient's motor function remained stable, and no motor fluctuation developed. Moreover, the patient had not experienced any further cognitive decline, and she could perform her usual work and daily activities again.

Discussion

The late neurological deterioration in BPAN typically occurs during the mid‐twenties, and, up to date, the oldest reported age of deterioration is 43 years, ⁶ , ⁸ making this the oldest case reported. Skewed X inactivation and mosaicism are thought to contribute to BPAN's clinical heterogeneity, ³ , ⁵ , ⁶ and we hypothesize that these two factors are a key reason for the relatively mild phenotype and late‐onset neurological deterioration in our patient.

In the later stage of BPAN, one can visualize a characteristic pattern on MRI with predominant bilateral brain iron accumulation within the substantia nigra and milder deposition in the globus pallidus. Interestingly, the predominance of iron deposition within the substantia nigra compared to the globus pallidus distinguishes BPAN from other NBIA disorders like pantothenate kinase‐associated neurodegeneration (PKAN), where iron deposits predominate in the globus pallidus. ¹ , ² , ⁴ Additionally, a hyperintense “halo sign” may be seen surrounding the normal‐appearing hypointense substantia nigra on T1 sequences. This represents neuromelanin released from degenerating dopaminergic neurons, and it is pathognomonic of BPAN. ⁴ , ⁹

As this case illustrates, there is usually a good response to dopaminergic drugs since the presynaptic nigrostriatal pathway is predominantly involved, although it has been reported that early motor fluctuations and dyskinesias can develop in up to 75% of patients during follow‐up. ⁴ , ⁹ , ¹⁰ Moreover, the patient exhibited a good and maintained response to botulinum toxin for spasticity, a finding that has not been reported so far in these patients.

This case contributes to the expansion of BPAN's clinical phenotype, highlighting the importance of seeking this diagnosis as patients can improve with dopaminergic and botulinum toxin therapy.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution, D. Patient care, E. Evaluation of genetic findings; (2) Statistical Analysis: A. Design, B. Execution, C. Review, and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review, and Critique.

R.C.: 1A, 1B, 1C, 1D, 3A

G.O.S.: 3B

I.R.B.: 3B

A.M.V.: 3B

B.R.S.: 1E, 3B

S.B.: 1E, 3A, 3B

J.K.: 3B

J.P.: 1A, 1B, 1C, 1D, 3B

Disclosures

Ethical Compliance Statement: All investigations performed in this family were done during clinical practice and care of the patient; therefore, ethics committee approval was not sought. The authors confirm that written informed consent for the publication of the medical data and the video was obtained and documented by the patient. Written consent is with the authors. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months: R.C., G.O.S., I.R.B., A.M.V., B.R.S., and S.B. declares that there are no additional disclosures to report. J.K. has received honoraria for advisory boards or lecturing from Teva, Zambon, UCB, Bial, General Electric, Sanofi, and Roche. J.P. has received honoraria for advisory boards or lecturing from Zambon, Abbvie, Bial, Ipsen, and UCB.