Compound heterozygote mutations in SPG7 in a family with adult-onset primary lateral sclerosis.
OBJECTIVE
To identify the genetic defect for adult-onset primary lateral sclerosis (PLS) in a family with 5 patients.


METHODS
Whole-exome sequencing was performed to identify the shared genetic variants in 3 affected members in a PLS family with 5 affected individuals. Sanger sequencing was used for validation of the variants and for cosegregation analysis. Mitochondrial activity for both patients and unaffected siblings was measured using a SeaHorse metabolic analyzer.


RESULTS
Whole-exome sequencing and subsequent cosegregation analysis demonstrated that compound heterozygous missense variants L695P and I743T in SPG7 were the only mutations cosegregating with the disease in an autosomal recessive fashion in this family. The parents and siblings are genetically heterozygous and clinically unaffected. Functional studies suggested that the PLS-associated SPG7 mutants affect mitochondrial function when glucose is reduced.


CONCLUSIONS
Compound heterozygote mutations in SPG7 are associated with adult-onset PLS, extending the spectrum of SPG7-linked neurologic diseases. Patients with the PLS phenotype should have genetic testing for paraplegin, especially when the condition is familial.
Department of Histology and Embryology (Y.Y., L.Z.), Hebei Medical University, China; Division of Neuromuscular Medicine (Y.Y., K.A., E.R., J.H.N., H.-X.D., N.S., T.S.), Davee Department of Neurology and Clinical Neurosciences and Department of Pharmacology (T.J.L.), Northwestern University Feinberg School of Medicine, Chicago, IL; Department of Neurology (D.L.) and Department of Pediatrics (P.M.A.S.), the Perelman School of Medicine, University of Pennsylvania, Philadelphia; and Department of Neurology (K.A.S.) and The Center for Applied Genomics (P.M.A.S.), The Children's Hospital of Philadelphia, PA.
Yi
Y
Yang
Department of Histology and Embryology (Y.Y., L.Z.), Hebei Medical University, China; Division of Neuromuscular Medicine (Y.Y., K.A., E.R., J.H.N., H.-X.D., N.S., T.S.), Davee Department of Neurology and Clinical Neurosciences and Department of Pharmacology (T.J.L.), Northwestern University Feinberg School of Medicine, Chicago, IL; Department of Neurology (D.L.) and Department of Pediatrics (P.M.A.S.), the Perelman School of Medicine, University of Pennsylvania, Philadelphia; and Department of Neurology (K.A.S.) and The Center for Applied Genomics (P.M.A.S.), The Children's Hospital of Philadelphia, PA.
Lei
L
Zhang
Department of Histology and Embryology (Y.Y., L.Z.), Hebei Medical University, China; Division of Neuromuscular Medicine (Y.Y., K.A., E.R., J.H.N., H.-X.D., N.S., T.S.), Davee Department of Neurology and Clinical Neurosciences and Department of Pharmacology (T.J.L.), Northwestern University Feinberg School of Medicine, Chicago, IL; Department of Neurology (D.L.) and Department of Pediatrics (P.M.A.S.), the Perelman School of Medicine, University of Pennsylvania, Philadelphia; and Department of Neurology (K.A.S.) and The Center for Applied Genomics (P.M.A.S.), The Children's Hospital of Philadelphia, PA.
David R
DR
Lynch
Department of Histology and Embryology (Y.Y., L.Z.), Hebei Medical University, China; Division of Neuromuscular Medicine (Y.Y., K.A., E.R., J.H.N., H.-X.D., N.S., T.S.), Davee Department of Neurology and Clinical Neurosciences and Department of Pharmacology (T.J.L.), Northwestern University Feinberg School of Medicine, Chicago, IL; Department of Neurology (D.L.) and Department of Pediatrics (P.M.A.S.), the Perelman School of Medicine, University of Pennsylvania, Philadelphia; and Department of Neurology (K.A.S.) and The Center for Applied Genomics (P.M.A.S.), The Children's Hospital of Philadelphia, PA.
Thomas
T
Lukas
Department of Histology and Embryology (Y.Y., L.Z.), Hebei Medical University, China; Division of Neuromuscular Medicine (Y.Y., K.A., E.R., J.H.N., H.-X.D., N.S., T.S.), Davee Department of Neurology and Clinical Neurosciences and Department of Pharmacology (T.J.L.), Northwestern University Feinberg School of Medicine, Chicago, IL; Department of Neurology (D.L.) and Department of Pediatrics (P.M.A.S.), the Perelman School of Medicine, University of Pennsylvania, Philadelphia; and Department of Neurology (K.A.S.) and The Center for Applied Genomics (P.M.A.S.), The Children's Hospital of Philadelphia, PA.
Kreshnik
K
Ahmeti
Department of Histology and Embryology (Y.Y., L.Z.), Hebei Medical University, China; Division of Neuromuscular Medicine (Y.Y., K.A., E.R., J.H.N., H.-X.D., N.S., T.S.), Davee Department of Neurology and Clinical Neurosciences and Department of Pharmacology (T.J.L.), Northwestern University Feinberg School of Medicine, Chicago, IL; Department of Neurology (D.L.) and Department of Pediatrics (P.M.A.S.), the Perelman School of Medicine, University of Pennsylvania, Philadelphia; and Department of Neurology (K.A.S.) and The Center for Applied Genomics (P.M.A.S.), The Children's Hospital of Philadelphia, PA.
Patrick M A
PM
Sleiman
Department of Histology and Embryology (Y.Y., L.Z.), Hebei Medical University, China; Division of Neuromuscular Medicine (Y.Y., K.A., E.R., J.H.N., H.-X.D., N.S., T.S.), Davee Department of Neurology and Clinical Neurosciences and Department of Pharmacology (T.J.L.), Northwestern University Feinberg School of Medicine, Chicago, IL; Department of Neurology (D.L.) and Department of Pediatrics (P.M.A.S.), the Perelman School of Medicine, University of Pennsylvania, Philadelphia; and Department of Neurology (K.A.S.) and The Center for Applied Genomics (P.M.A.S.), The Children's Hospital of Philadelphia, PA.
Eanna
E
Ryan
Department of Histology and Embryology (Y.Y., L.Z.), Hebei Medical University, China; Division of Neuromuscular Medicine (Y.Y., K.A., E.R., J.H.N., H.-X.D., N.S., T.S.), Davee Department of Neurology and Clinical Neurosciences and Department of Pharmacology (T.J.L.), Northwestern University Feinberg School of Medicine, Chicago, IL; Department of Neurology (D.L.) and Department of Pediatrics (P.M.A.S.), the Perelman School of Medicine, University of Pennsylvania, Philadelphia; and Department of Neurology (K.A.S.) and The Center for Applied Genomics (P.M.A.S.), The Children's Hospital of Philadelphia, PA.
Kimberly A
KA
Schadt
Department of Histology and Embryology (Y.Y., L.Z.), Hebei Medical University, China; Division of Neuromuscular Medicine (Y.Y., K.A., E.R., J.H.N., H.-X.D., N.S., T.S.), Davee Department of Neurology and Clinical Neurosciences and Department of Pharmacology (T.J.L.), Northwestern University Feinberg School of Medicine, Chicago, IL; Department of Neurology (D.L.) and Department of Pediatrics (P.M.A.S.), the Perelman School of Medicine, University of Pennsylvania, Philadelphia; and Department of Neurology (K.A.S.) and The Center for Applied Genomics (P.M.A.S.), The Children's Hospital of Philadelphia, PA.
Jordan H
JH
Newman
Department of Histology and Embryology (Y.Y., L.Z.), Hebei Medical University, China; Division of Neuromuscular Medicine (Y.Y., K.A., E.R., J.H.N., H.-X.D., N.S., T.S.), Davee Department of Neurology and Clinical Neurosciences and Department of Pharmacology (T.J.L.), Northwestern University Feinberg School of Medicine, Chicago, IL; Department of Neurology (D.L.) and Department of Pediatrics (P.M.A.S.), the Perelman School of Medicine, University of Pennsylvania, Philadelphia; and Department of Neurology (K.A.S.) and The Center for Applied Genomics (P.M.A.S.), The Children's Hospital of Philadelphia, PA.
Han-Xiang
HX
Deng
Department of Histology and Embryology (Y.Y., L.Z.), Hebei Medical University, China; Division of Neuromuscular Medicine (Y.Y., K.A., E.R., J.H.N., H.-X.D., N.S., T.S.), Davee Department of Neurology and Clinical Neurosciences and Department of Pharmacology (T.J.L.), Northwestern University Feinberg School of Medicine, Chicago, IL; Department of Neurology (D.L.) and Department of Pediatrics (P.M.A.S.), the Perelman School of Medicine, University of Pennsylvania, Philadelphia; and Department of Neurology (K.A.S.) and The Center for Applied Genomics (P.M.A.S.), The Children's Hospital of Philadelphia, PA.
Nailah
N
Siddique
Department of Histology and Embryology (Y.Y., L.Z.), Hebei Medical University, China; Division of Neuromuscular Medicine (Y.Y., K.A., E.R., J.H.N., H.-X.D., N.S., T.S.), Davee Department of Neurology and Clinical Neurosciences and Department of Pharmacology (T.J.L.), Northwestern University Feinberg School of Medicine, Chicago, IL; Department of Neurology (D.L.) and Department of Pediatrics (P.M.A.S.), the Perelman School of Medicine, University of Pennsylvania, Philadelphia; and Department of Neurology (K.A.S.) and The Center for Applied Genomics (P.M.A.S.), The Children's Hospital of Philadelphia, PA.
Teepu
T
Siddique