VITAMIN D DEPENDENCY

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Ped kiirics

VOLUME 45 MARCH 1970 NUMBER 3, PART I

COMMENTARY

VITAMIN

D DEPENDENCY

A

CONDITION still quite unfamiliar to many

physicians is discussed in this is-sue of PEDIATRICS.1 The disease, called

“Vi-tamin-D-dependent rickets” in the

accom-panying article, was first segregated from

the array of “Vitamin-D-resistant rickets”

by Fraser and Salter2 (Type III, A, ii, in

their classification), and by Prader and col-leagues (hereditary

pseudo-vitamin-D-de-ficiency rickets, in their terminology). The condition is characterized by signs and symptoms which appear in the first year of life, and which are easily mistaken for those

of severe (Stage III) vitamin D deficiency.

As revealed in typical case reports of the

condition,3’5 manifestations include muscu-lar weakness, convulsions, severe rickets,

growth

failure, hypophosphatemia, low or

normal

total

serum

calcium,

mild renal tu-bular acidosis, and hyperaminoaciduria.

Vi-tamin D dependency responds dramatically to vitamin D2 when given in the appropri-ate daily dose, which is about 100 times the

normal requirement. A persistent need for

this large amount of the vitamin has been

observed throughout childhood, and it may

persist for the patient’s life-time; it is this

feature which invokes the term

“depen-dency.”

The incidence of vitamin D dependency,

which is inherited as a simple autosomal re-cessive trait,5’6 is higher than once suspected,

and two groups working in Toronto and

Montreal each now have half a dozen

pa-tients under their care.6 Therefore, it is all

the more important that vitamin D

depen-dency be distinguished from advanced

vi-tamin D deficiency, an acquired condition which is still all too common.4 This can be

done most easily when the family history

reveals other affected siblings with persis-tent rickets, and when there is a history of normal vitamin D intake in infancy (i.e.,

about 400 I.U. daily) prior to the onset of

symptoms. In both conditions there is evi-dence for secondary hyperparathyroidism

with attendant changes in bone and renal

tubular function,’’ which serves to

dis-tinguish them from other forms of

hypo-phosphatemic rickets caused by primary

disorders of phosphate transport in the renal tubule. What then is common to the defi-ciency and dependency states, and yet why are they different; and what is the signifi-cance of the current paper in PEDIATRIcs?

The understanding of these two

condi-tions, and of other forms of vitamin D

re-sponsive rickets, lies in new information on

the metabolism and action of vitamin D.511

The lipid-soluble substances, known to most

physicians as vitamin D2 (ergocalciferol)

and vitamin Dt (cholecalciferol) are formed

from provitamins by the opening of ring B

under the influence of ultraviolet radiation.

The vitamin is then bound to globulin and

carried in plasma to the liver where it tinder-goes hydroxylation, to form the

correspond-ing polar 25-hydroxy derivatives (25-HEC

and 25-HCC), which are the forms of the

vitamin destined to carry out its biological

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362

VITAMIN D DEPENDENCY

functions. After hepatic synthesis of its

ac-tive form, the vitamin is again transported in plasma by 2 globulin, until it is bound to the

nuclear

membrane of intestinal epithelial cells. Thereafter, by mechanisms still

requir-ing elucidation, it initiates synthesis of a

specific

messenger

RNA, by activating a por-lion of nuclear DNA

(

gene or genes

)

. The

m-RNA in its turn initiates synthesis of a

cytoplasmic protein

(

or proteins

)

whose

major site of action is in the brush border of intestinal epithelial cells. This

protein

which

has been isolated and some of its properties

characterized from chick intestinal

mu-cosa,12 mediates calcium transport from the

brush border to the antiluminal border,

and hence to the blood. The vitamin also

stimulates a calcium-dependent ATPase in

brush border which is important in

aug-menting initial rates of calcium uptake.9 The

25-hydroxy

derivative of vitamin D has a third important effect. It can act directly on

bone

in physiological

doses

to release

cal-cium

and phosphate ions;13 this action is

very

similar

to that of parathyroid

hormone

and it is inhibited by calcitonin.

It should be remembered when

interpret-ing the clinical manifestations of the

de-ficiency and dependency states, that

para-thyroid

hormone

can

stimulate

intestinal

transport of calcium and mobilize calcium from bone only in the presence of vitamin

D.14 On the other hand, vitamin D, in any

form, is not necessary for the inhibitory ef-fect of parathyroid hormone on renal

tubu-lar conservation of phosphate and amino

acids.4’7’5 These complicated relationships

between vitamin and hormone action on

cal-cium metabolism have one important

objec-tive, namely, to maintain the extracellular

concentration of calcium ion within the

nar-row range wherein it modulates membrane

activity in many tissues of the body

includ-parathyroid response in an attempt to

main-tam calcium levels in body fluids even at

the expense of bone mineralization and of

renal tubular function. Any impairment in

the conversion of vitamin D to the

biologi-cally important 25-hydroxy derivative, or

any inhibition of its binding to the nuclear

membrane

will have an effect on calcium nutrition similar to that of dietary deficiency

of

the vitamin.

At the present time, it is useful to consider

vitamin D dependency as a Mendelian trait

affecting the endogenous metabolism of

vita-mm. D. This hypothesis can now be tested.

The paper by the Toronto group1 tells us

that

in

vitamin

D dependency there is a spe-cific intestinal transport defect affecting

cal-cium ion alone. Whereas this might be

con-sidered another “inborn error of membrane

transport,” we are now in a position to con-sider the trait as a potential inborn error of vitamin D metabolism. Two

clinical

features

of the trait inform us further on the

possi-bilities for productive research on this di-sease in the future. First, when sufficient

vitamin D1 or D3 is given to

vitamin-D-dependent patients, an immediate regression of the fully expressed phenotype occurs; this indicates that normal calcium transport pro-tein( s) can be synthesized endogenously

under suitable conditions. Secondly, the

vitamin D requirement is permanently 100

times greater than normal. This suggests

that vitamin D dependency is either a

“leaky” mutant in which high concentrations of vitamin precursor are necessary to initiate

synthesis of a small amount of the

25-hydroxy derivative; or the trait represents a

change in Km of the binding site for

25-hydroxy

derivative on the nuclear

mem-brane which high concentrations of the

25-hydroxy derivative can offset.

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formation on the treatable hereditary

vita-min dependencies of man,’6’17 and to

pre-scribe for such patients effectively and

rationally.

CHARLES R. SciuvER, M.D.

The deBelle Laboratory for

Biochemical Genetics The McGill University-Montreal

Children’s Hospital Research

Institute

2300 Tupper Street

Montreal 25, Quebec

REFERENCES

1. Hamilton,

J.

R., Harrison,

J.,

Fraser, D., Radde, I., Morecki, R., and Paunier, L.: The small intestine in vitamin D dependent rickets. PEDIATRICS, 45:364, 1970.

2. Fraser, D., and Salter, R. B.: The diagnosis and management of the various types of rickets. Pediat. Clin. N. Amer., 417, May, 1958. 3. Prader, Von A., hug, R., and Heierli, E.: Eine

besondere form der prim#{228}ren vitamin-D re-sistenten rachitis mit hypocalcamie und au-tosomal-dominantem erbgang: die heredi-tare pseudo-mangelrachitis. Helv. Paediat. Acta, 16:452, 1961.

4. Fraser, D., Kooh, S. W., and Scriver, C. R.: Hyperparathyroidism as the cause of

hy-peraminoaciduria and phosphaturia in human

vitamin D deficiency. Pediat. Res., 1:425,

1967.

5. Stoop,

J.

W., Schraagen, M. J. C., and Tiddens, H. A. W. M.: Pseudo vitamin D deficiency

rickets. Acta Paediat. Scand., 56:607, 1967. 6. Fraser, D., and Scriver, C. H.: Unpublished

ob-servations.

7. Crose,

J.,

and Scriver, C. H.: Parathyroid de-pendent phosphaturia and aminoaciduria in the vitamin D deficient rat. Amer. J. Physiol.,

214:370, 1968.

8. Norman, A. \V.: The mode of action of vitamin D. Biol. Rev., 43:97, 1968.

9. DeLuca, H. F.: Recent advances in the me-tabolism and function of vitamin D. Fed. Proc., 28:1678, 1969.

10. DeLuca, H. F.: Current concepts: Vitamin D. New Eng. J. Med., 281:1103, 1969.

11. Kimberg, D. V.: Effects of vitamin D and

steroid hormones on the active transport of

calcium by the intestine. New Eng.

J.

Med., 280: 1396, 1969.

12. Wasserman, R. H.: Calcium transport by the intestine: A model and comment on vitamin D action. CaIc. Tiss. Res., 2:301, 1968. 13. Trummel, C. L., Raisz, L. C., Blunt,

J.

W., and

DeLuca, H. F.: 25-hydroxycholecalciferol: Stimulation of bone resorption in tissue cul-tare. Science, 163:1450, 1969.

14. Rasmussen, H., and DeLuca, H. F.: Calcium homeostasis. Ergehn. Physiol., 53:108, 1963. 15. Amaud, C., Rasmussen, H., and Anast, C.:

Further studies on the interrelationship be-tween parathyroid hormone and vitamin D.

J. Clin. Invest., 45:1955, 1966.

16. Rosenberg, L. E.: Inherited amino acidopathies demonstrating vitamin dependencies. New Eng. J. Med., 281:146, 1969.

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1970;45;361

Pediatrics

Charles R. Scriver