We describe four SPG11 patients with confirmed KIAA1840
mutations and a clinical picture of a progressive spastic paraparesis complicated by cognitive deterioration, cerebellar and extrapyramidal signs, peripheral neuropathy/neuronopathy, and central retinal degeneration. All four patients had characteristic MRI abnormalities previously described in SPG11.9
In addition, 3 of our 4 patients showed abnormalities in CSF neurotransmitter metabolite concentrations: low concentration of HVA, the main metabolite in the catabolic pathway of dopamine; and low levels of BH4. While other SPG11 patients with mainly extrapyramidal signs have been described,4
CSF neurotransmitter metabolite analysis has not been reported in these patients, although one study illustrated functional dopamine deficits on SPECT imaging.3, 4
It is unlikely that these four subjects with established SPG11 mutations additionally had a primary neurotransmitter disorder.7
The CSF profile of neurotransmitters of the patients is not classical for any known primary disorder. Specifically, aromatic L-amino acid decarboxylase (AADC) deficiency would be expected to have elevated 3-O-methyldopa with normal BH4, and tyrosine hydroxylase (TH) deficiency would be expected to have normal BH4 in the presence of decreased HVA.10
In addition, other abnormalities of biopterin metabolites might be seen, such as decreases in neopterin in addition to BH4 (GTP cyclohydrolase deficiency), or increases in neopterin (sepiapterin reductase deficiency or 6-pyruvoyltetrahydropterin synthase or PTPS deficiency).8, 10, 11
The mechanism leading to neurotransmitter abnormalities in SPG11 patients is not known. The function of spatacsin itself is not well understood, although the protein has been associated with cytoskeleton, endoplasmic reticulum and vesicles involved in protein trafficking, suggesting a role in axonal transport.12
We speculate that the disruption of these systems could also disturb the physiological neurotransmitter synthesis and transport toward synapses leading to the secondary neurotransmitter abnormalities, although this could also be due to effects of non-specific neurodegeneration and cellular loss. 123I-ioflupane SPECT imaging in two cases reported by Anheim et al.3, 4
demonstrated bilateral reduction of striatal ligand uptake consistent with dysfunction of nigro-striatal innervation.
Although further studies are necessary to understand the origin of neurotransmitter abnormalities in SPG11, this finding in combination with extrapyramidal signs led us to start supplementation of dopamine and tetrahydrobiopterin pathways with L-dopa/carbidopa and sapropterin. We saw at least temporary improvement of motor symptoms in 4/4 patients. Benefits from L-Dopa therapy in SPG-11-associated juvenile parkinsonism have been previously described.3, 4
Our cases further support the idea of an imbalance of the normal dopaminergic circuits in SPG11 patients and the potential benefit of supplemental treatment, in particular in the presence of extra pyramidal features. The observations in this report cover a period of approximately two years, thus, the effects over a longer time span remain unclear for this patient group, and larger, adequately controlled studies are need to determine the benefits of this type of therapy.
Of note, the frequency of neurotransmitter abnormalities in SPG11 is unknown, and the relationship between identified secondary neurotransmitter abnormalities and a response to supplementation has not been explored. Our patient 3, who showed normal CSF neurotransmitters concentrations but responded to supplementation, presented milder symptoms than his brother (patient 2). It is unknown why his neurotransmitters differed from the other patients. It is conceivable that measurable deficits of dopamine and tetrahydrobiopterin pathways are a late finding, and earlier undetectable deficits may result in clinical manifestations and be amendable to supplementation.