Clinical Description
Neurologic findings
Childhood onset. In the childhood-onset form of dystonia/parkinsonism, hypermanganesemia, polycythemia, and chronic liver disease,
affected individuals present with neurologic signs between ages two and 15 years. Many become wheelchair bound in their teens.
The neurologic signs and symptoms of the childhood-onset form are primarily extrapyramidal and include dystonia, dysarthria, and rigidity. Four-limb dystonia manifests with difficulties walking and a high-stepping gait ("cock walk gait"), dystonic posturing, and painful extensor spasms. Fine motor impairment causes problems with writing and drawing and inability to perform rapid alternating movements of the hands (dysdiadochokinesis). Dystonia of the tongue can lead to dysarthria [
Quadri et al 2012,
Tuschl et al 2012,
Quadri et al 2015].
Isolated corticospinal tract involvement has been described in one
affected individual. Typical neurologic signs of spastic paraparesis (e.g., spasticity, hyperreflexia, extensor plantar responses) were found [
Gospe et al 2000].
Adult onset.
Quadri et al [2012] reported two brothers who presented at ages 47 years and 57 years with progressive gait disturbance and bradykinesia. Neurologic examination showed features of parkinsonism including hypomimia, monotone speech, mild rigidity, global bradykinesia, wide-based gait with freezing and starting hesitation, and moderate postural instability without evidence of tremor, dystonia, or cerebellar or pyramidal disturbances. Treatment with L-dopa and dopamine agonists did not improve neurologic findings.
Sensory-motor axonal polyneuropathy has been described in two
affected individuals with the late-onset neurologic presentation [
Quadri et al 2012].
Hypermanganesemia: Whole-blood manganese concentrations are elevated in all affected individuals.
Note: Blood manganese concentrations of heterozygotes (i.e., carriers of one SLC30A10 pathogenic variant) are within normal limits or are mildly elevated. Gospe et al [2000] reported a borderline high blood manganese concentration of 380 nmol/L in an obligate heterozygous parent and Tuschl et al [2012] reported levels between 380 and 649 nmol/L in three heterozygous parents (normal: <320 nmol/L).
Polycythemia. All affected individuals reported to date had polycythemia at the time of diagnosis. Polycythemia can precede the onset of neurologic manifestations and, therefore, affected individuals often undergo repeat phlebotomies prior to recognition of the correct diagnosis [Quadri et al 2012, Tuschl et al 2012]. Polycythemia has been described in affected children from age three years; earlier presentation of polycythemia cannot be ruled out because of insufficient data. Individuals in whom neurologic symptoms do not manifest until late adulthood have had polycythemia since as early as the third decade. Polycythemia can resolve upon treatment with chelation therapy or iron. There is evidence from one patient whose polycythemia resolved without treatment during advanced stage of disease [Lechpammer et al 2014].
Liver disease. The spectrum of hepatic involvement ranges from mild hepatomegaly to hepatic failure in early adulthood [Tuschl et al 2012]. However, pure neurologic phenotypes presenting with dystonia alone have been reported [Quadri et al 2012].
In the majority of affected individuals, transaminases are mildly elevated [Quadri et al 2012, Tuschl et al 2012]. To date, three affected individuals died of complications of liver cirrhosis between ages 18 and 46 years. As most of the affected individuals known to the authors are still in their teens or early adulthood, no long-term follow-up data are available.
Significant phenotypic variability even within the same family is apparent: The two brothers reported by Quadri et al [2012], who are now in their sixties and severely affected by dystonia, did not show hepatic involvement. Both had normal liver function and liver ultrasound examination throughout their lives. However, while the affected sister had minimal neurologic involvement, she developed liver cirrhosis in the third decade and died of liver failure at age 46 years.
Intellect appears normal in all affected individuals. Quadri et al [2012] described one individual who developed cognitive and behavioral problems, thought to be alcohol related. While environmental manganese exposure is known to cause cognitive and psychiatric disturbances (so called "manganese madness") including emotional lability, hallucinations, and compulsive behavior [Racette et al 2012], this has not yet been observed in patients with dystonia/parkinsonism, hypermanganesemia, polycythemia, and chronic liver disease.
Pica. Several affected individuals had pica during early childhood [Brna et al 2011; Brna, unpublished data].
Darker skin tone. Some affected individuals have been described to have a purple or dark skin discoloration to an extent that parents are able to distinguish affected and unaffected children prior to the manifestation of clinical symptoms [Authors, unpublished data].
Pathology. Post-mortem studies in an individual with SLC30A10 deficiency showed yellow-grey mottling of the basal ganglia associated with severe neuronal loss, astrocytosis, myelin loss, spongiosis, and rhodanine-positive deposits particularly in the globus pallidus, while other basal ganglia were affected to a lesser extent. Gliosis of the white matter and axonal loss of the corticospinal tracts were observed [Lechpammer et al 2014].