Child Neurology: Spastic paraparesis and dystonia with a novel ADCY5 mutation

Initial evaluation and diagnostic approach for multiple abnormal movements

When a patient presents with multiple abnormal movements, the most important first step is to correctly define the phenomenology. This includes recognition of hyperkinetic movements such as chorea, dystonia, and tremor, as well as hypokinetic movements such as bradykinesia and akinesia. Once the movements are defined, the clinician should identify the most prominent abnormal movement, as this will guide the differential diagnosis and workup. The age at onset, progression of symptoms, and accompanying clinical features may add additional clues to the diagnosis. A detailed family history, including presence of consanguinity, should be obtained to aid in identifying a mode of inheritance: autosomal dominant, autosomal recessive, X-linked recessive, or sporadic. Based on the phenomenology, most prominent abnormal movement, clinical and family histories, and accompanying examination features, a proper differential diagnosis can be created and a workup initiated.⁷ It is, however, important to realize that these steps are merely a guide. If an initial workup is unrevealing for the dominant abnormal movement, one should consider a workup based on the accompanying abnormal movements.

In our case, both spastic paraparesis and dystonia were prominent abnormal neurologic findings. Spastic paraparesis is formally defined as lower limb spasticity and weakness. While spastic paraparesis is not usually considered a movement disorder, it can lead to abnormal gait patterns and abnormal movements. Dystonia refers to “sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both.”^8,9 When dystonia and spastic paraparesis coexist, identifying the dominant clinical symptom, along with the age at onset, can help guide the workup.⁸ For example, if childhood-onset spastic paraparesis is the most prominent symptom, an initial workup should include MRI of the brain and spinal cord in order to identify structural lesions or white matter abnormalities. In contrast, if childhood-onset dystonia is the most prominent symptom, the initial workup should include MRI of the brain as well as CT imaging of the head to evaluate for basal ganglia calcifications. In addition, screening for potentially treatable diseases (table) is highly advisable for patients with spastic paraparesis or dystonia.

Differential diagnosis for childhood-onset spastic paraparesis and dystonia

The differential diagnosis for childhood-onset spastic paraparesis and dystonia includes several conditions (table). If present, additional clinical features may assist in narrowing the differential diagnosis further. In our patient, we considered metabolic disorders such as Krabbe disease, metachromatic leukodystrophy, cerebral folate deficiency, cerebrotendinous xanthomatosis (CTX), biotinidase deficiency, and primary monoamine neurotransmitter disorders.¹⁰ It is important to recognize that primary monoamine neurotransmitter disorders (commonly referred to as dopa-responsive dystonias) improve with treatment of levodopa, and that these disorders may also present with a phenotype that resembles spastic paraparesis. Finally, Wilson disease should be considered as many phenotypes, including those with multiple abnormal movements, have been described in association with this treatable disease.

Genetic testing for spastic paraparesis and dystonia

There are many options available for genetic testing, including testing for single genes, gene panels, whole exome sequencing, and WGS. If spastic paraparesis is a prominent finding on examination, then genetic testing with an HSP panel is an appropriate first step. Likewise, if dystonia is believed to be a more prominent finding, then a dystonia panel may be considered first for genetic testing. If no pathogenic variants are identified through panel testing, then we recommend considering WGS since it is now readily available for clinical use.

In our patient, the first genetic test that was ordered was an HSP panel, which did not reveal any pathogenic variants. We then proceeded to WGS, which revealed a novel variant in the ADCY5 gene. This variant was determined to be likely pathogenic based on several criteria. The variant had not been reported in large population databases (1000 Genomes or the ExAC databases), thus indicating it is not a common variant. In addition, this variant was predicted to cause dysfunction to the ADCY5 gene through in silico analysis (damaging by SIFT, probably damaging by PolyPhen, and a CADD score of 22.2). Parental studies, including maternal and paternal identity testing, indicated the variant arose de novo, meaning the variant was not present in either parent. Previously reported pathologic variants within the ADCY5 gene produced dyskinesias, chorea, or dystonia in affected patients.^1,–,5 For these combined reasons, the variant was predicted to be likely pathogenic by the American College of Medical Genetics and Genomics guidelines (PS2, PM2, PP3, PP4).¹¹

ADCY5 gene mutations and clinical phenotypes

The ADCY5 gene encodes adenylyl cyclase 5, which converts adenosine triphosphate into cyclic adenosine monophosphate.¹² Pathogenic ADCY5 variants are usually expressed in an autosomal dominant pattern, although an autosomal recessive inheritance pattern has recently been described.^1,2 It is important to recognize that when there is no family history of a similar phenotype, it is possible that a pathogenic mutation may arise de novo as well.

Neurologic symptoms associated with an ADCY5 gene mutation were first described in a German family, which was originally classified as autosomal dominant familial dyskinesia with facial myokymia.² Subsequently, additional individuals with ADCY5 genetic variants have been described. These individuals most frequently exhibit hyperkinetic movements, especially chorea.^3,4 Other common clinical features include axial hypotonia, facial chorea/dystonia, diurnal exacerbations of movement disorders, minimal to no cognitive impairment, and little to no progression of symptoms.⁴ Of these common features, our patient only exhibited diurnal exacerbations of movement disorders that were described as large jerks of her legs at night. She had less common features of developmental delay/cognitive impairment and progression of her symptoms. For a review of ADCY5 phenotypes, see “Phenotypic insights into ADCY5-associaed disease.”⁵ Interestingly, a recent case report describes a woman with a phenotype more closely resembling our patient: spastic paraparesis, dystonia, hyperreflexia, and progression of symptoms.⁶ This patient had a missense mutation within the M2 domain of the ADCY5 gene, while our patient's mutation lies within the M1 domain. Sensory symptoms have not been well-described in ADCY5 gene mutation patients. However, since no other cause was identified in our patient, we postulate that her sensory symptoms may be related to her gene mutation.

Brain MRI abnormalities were not reported in the initial cases of ADCY5 gene mutations and are not typically associated with the disorder. However, one patient with an ADCY5 pathogenic variant exhibited hypointensities within the globus pallidus interna bilaterally, but this pattern was different from that seen in our patient.⁴ In addition, the recently reported case with a spastic paraparesis phenotype did not have abnormalities on brain MRI.⁶ Because the finding in our patient of white matter involvement on brain MRI is not a common feature of ADCY5 mutations, we evaluated for other causes of leukoencephalopathy. However, none was found, and thus we suspect this finding may be attributable to the ADCY5 variant.

Treatment options for ADCY5-related dyskinesias

There is currently no specific treatment for ADCY5-related dyskinesias. Medications are selected based on the specific abnormal movement but have resulted in limited success in ADCY5-associated dyskinesias.¹³ Preventative treatment should be utilized through a multidisciplinary approach with physical therapy and occupational therapy to prevent future complications from immobility and spasticity.

When evaluating a child with multiple abnormal movements, accurate identification of the phenomenology guides further workup and management. For a patient presenting with childhood-onset spastic paraparesis and dystonia, MRI should be included in the initial workup. In addition, treatable conditions need to be considered for these patients, which includes dopa-responsive dystonia, CTX, vitamin E deficiency, Wilson disease, and biotin deficiency, among others (table). When an etiology is not revealed, WGS may be a helpful tool to identify rare disorders. With this additional case of a spastic paraparesis and dystonia phenotype associated with an ADCY5 gene mutation, we propose the addition of ADCY5 to spastic paraparesis gene panels.