PMC

Photographs of the hands of Case 33 with ZFYVE26/SPG15 mutation (homozygous p.R1378* mutation). Showing the adducted thumbs that are similar to those seen in MASA (mental retardation, aphasia, shuffling gait and adducted thumbs) syndrome. Age of patient: 34 years.

Reverse transcription PCR to assess SPG11 mRNA expression in fibroblasts. Wide expression is seen across SPG11 affected and control fibroblasts. Numbers in red are SPG11 affected cases from and . Letters in blue are controls from . GAPDH = housekeeping gene glyceraldehyde 3-phosphate dehydrogenase.

High-throughput next-generation sequencing can identify disease-causing mutations in extremely heterogeneous disorders. Kara et al . investigate a series of 97 index cases with complex hereditary spastic paraplegia (HSP). They identify SPG11 defects in 30 families, as well as mutations in other HSP genes and genes associated with disorders including Parkinson’s disease.

Analysis of markers for autophagy and lysosomal function in human fibroblast cells. ( A ) Fibroblast protein expression levels of LAMP1 and LC3 as compared to beta actin in SPG11 affected and control fibroblasts after starvation induced autophagy (overnight serum starvation, followed by 2.5 h amino acid starvation in low glucose). ( B ) Fibroblast protein expression levels of p62 and HSP70 as compared to beta actin in SPG11 affected and control fibroblasts after starvation induced autophagy (overnight serum starvation, followed by 2.5 h amino acid starvation in low glucose).

Overview of mutations identified in spastic paraplegia genes. ( A ) Pie chart showing the frequency of mutations in spastic paraplegia genes identified. The figures in brackets represent the number and percentage of cases respectively. ( B ) Frequencies of clinical features that were present in addition to the spastic paraplegia in SPG11 probands. ( C ) Frequencies of clinical features that were present in addition to spastic paraplegia in the spastic paraplegia patients with other mutations. In B and C the figures in brackets refer to the number of cases. ( D ) Diagram of the SPG11 gene with mutations identified in the present study. Grey arrows indicate novel and black arrows indicate previously reported mutations.

MRI features in patients with complex HSP. ( A ) Sagittal MRI of SPG11 patients showing progressive thinning of the corpus callosum and cerebral atrophy, which correlates with the progression of clinical features. ( i ) MRI from a healthy individual with labelling of the different parts of the corpus callosum. ( ii ) Case 5 at age 18 (mild disease). ( iii ) Case 8 at age 22 (mild-moderate disease). ( iv ) Case 17 at age 23 (moderate disease). ( v ) Case 10 at age 30 (severe disease). ( vi ) Case 16 age 32 (severe disease). ( vii ) Case 9 age 39 (severe disease). See for details of case numbers. ( B ) MRI of complex HSP cases. ( i ) Case 37 (age 24 years), SPG7 showing an axial MRI with high signal in the cerebral peduncles (arrow) and on coronal imaging ( ii ) and sagittal imaging (arrow) ( iii ) with thinning of the body of the corpus callosum (arrow). Case 33 (age 34 years) ( iv to vi ), SPG15 with thinning of the corpus callosum ( iv ) (arrow) and generalized atrophy with periventicular white matter abnormalities (arrow). ( C ) Sagittal MRI of FA2H patients. ( i–iii ) Case 32, age 32 years, slowly progressive with thinning of the corpus callosum, cerebellar and cortical atrophy. ( iv–vi ) Case 52, age 37 years, more rapid and severely affected: shows severe corpus callosum thinning, cerebellar and cerebral atrophy, but preserved white matter, similar to the Case 32.

Morphological findings of one nerve and four muscle biopsies in five genetically characterized patients with HSP. Patient with ZFYVE26/SPG15 mutation ( A and C ) and control individual ( B and D ). SPG11 mutation ( E ), SPG7 mutation ( F and G ). Semi-thin resin preparations stained with methylene blue azure—basic fuchsin ( A and B ) show a reduction of large myelinated fibre density in the patient’s biopsy, compared with a biopsy from age-matched control. Large fibre loss is further confirmed by electron microscopy ( C and D ), while unmyelinated fibres are better preserved. There is no evidence of active axonal degeneration, regeneration or demyelination and the overall picture is that of chronic axonal neuropathy. The muscle biopsies from three patients investigated for signs of denervation show varied appearances. In the biopsy from the patient with a known SPG11 mutation ( E ) there is predominance of type 1 fibres (yellow arrow, ATP pH4.3). In one patient with SPG7 mutation ( F ) the most significant finding in the muscle biopsy is that of several COX-deficient fibres (red arrows) seen on combined COX-SDH preparation. In another patient with SPG7 mutation ( G ) the biopsy confirms neurogenic change with evidence of previous denervation with re-innervation (blue arrow indicates a group of type 1 fibres, ATP pH4.3). Scale bars: A , B and E–H = 40 μm; C and D = 5 μm.